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1. Actin-independent exclusion of CD95 by PI3K/AKT signalling: Implications for apoptosis

Author

Michel Castroviejo, Jean-François Moreau, Mathieu Pizon, Patrick Legembre, Sébastien Tauzin, Hariniaina Rampanarivo, Benjamin Chaigne-Delalande, Sophie Daburon, Patrick Moreau, Université Bordeaux Segalen - Bordeaux 2, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Laboratoire de biogenèse membranaire (LBM), CHU Bordeaux [Bordeaux], INCa (projets libres recherche biomédicale), Cancéropole GO, Région Bretagne, Rennes Métropole, Ligue Contre le Cancer (Comités d'Ille-et-Vilaine/Morbihan/Côtes d'Armor/Maine et Loire), University of Rennes-1, Ligue Contre Le Cancer, Université de Rennes (UR), Microbiologie Fondamentale et Pathogénicité (MFP), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Fas-Associated Death Domain Protein, MESH: Membrane Microdomains, Apoptosis, MESH: Flow Cytometry, PI3K, Jurkat Cells, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, MESH: Jurkat Cells, MESH: Protein Kinase Inhibitors, Immunology and Allergy, FADD, Lipid raft, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, biology, Signal transducing adaptor protein, MESH: Fas-Associated Death Domain Protein, Flow Cytometry, Fas receptor, MESH: Antigens, CD95, Cell biology, Caspases, 030220 oncology & carcinogenesis, CD95, [SDV.IMM]Life Sciences [q-bio]/Immunology, biological phenomena, cell phenomena, and immunity, Wortmannin, Signal Transduction, Fas Ligand Protein, MESH: Mutation, MESH: Cell Line, Tumor, Morpholines, Blotting, Western, Immunology, MESH: Morpholines, MESH: Actins, Cell Line, 03 medical and health sciences, Membrane Microdomains, Cell Line, Tumor, Humans, MESH: Blotting, Western, fas Receptor, Protein Kinase Inhibitors, Protein kinase B, Lipid rafts, PI3K/AKT/mTOR pathway, 030304 developmental biology, Death domain, MESH: Humans, MESH: Caspases, MESH: Proto-Oncogene Proteins c-akt, Akt, MESH: Apoptosis, Cell Membrane, MESH: Multiprotein Complexes, Actin cytoskeleton, Actins, MESH: Fas Ligand Protein, MESH: Cell Line, Androstadienes, MESH: Chromones, Chromones, MESH: Phosphatidylinositol 3-Kinases, Multiprotein Complexes, MESH: Androstadienes, Mutation, biology.protein, Proto-Oncogene Proteins c-akt, MESH: Cell Membrane
Abstract

International audience; The immune system eliminates infected or transformed cells through the activation of the death receptor CD95. CD95 engagement drives the recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates and activates initiator caspases-8 and -10. The CD95-mediated apoptotic signal relies on the capacity to form the CD95/FADD/caspases complex termed the death-inducing signalling complex (DISC). Cells are classified according to the magnitude of DISC formation as either type I (efficient DISC formation) or type II (inefficient). CD95 localised to lipid rafts in type I cells, whereas the death receptor was excluded from these domains in type II cells. Here, we show that inhibition of both PI3K class IA and serine-threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal. Strikingly, these molecular events took place independently of CD95L and the actin cytoskeleton. Overall, these findings highlight that the oncogenic PI3K/Akt signalling pathway participates in maintaining cells in a type II phenotype by excluding CD95 from lipid rafts.

Published
2011
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2. Human CD4+invariant NKT cells are involved in antibacterial immunity againstBrucella suisthrough CD1d-dependent but CD4-independent mechanisms

Author

Sherri Dudal, Stéphanie Bessoles, Virginie Lafont, Gurdyal S. Besra, Françoise Sanchez, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie et Pathologie Cellulaire Infectieuse, Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cytotoxicity, Immunologic, Fas Ligand Protein, Brucella suis, MESH: Interferon-gamma, Immunology, Population, MESH: Antigens, CD4, Brucellosis, Cell Degranulation, Microbiology, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Immune system, MESH: Brucellosis, Humans, Immunology and Allergy, Macrophage, Cytotoxic T cell, fas Receptor, MESH: Cytotoxicity, Immunologic, education, MESH: Brucella suis, 030304 developmental biology, 0303 health sciences, education.field_of_study, MESH: Humans, biology, Tumor Necrosis Factor-alpha, Macrophages, MESH: Macrophages, MESH: Interleukin-4, Natural killer T cell, MESH: Fas Ligand Protein, MESH: Antigens, CD95, MESH: Natural Killer T-Cells, MESH: Antigens, CD1d, MESH: Tumor Necrosis Factor-alpha, CD1D, CD4 Antigens, MESH: Cell Degranulation, biology.protein, Natural Killer T-Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin-4, Antigens, CD1d, CD8, 030215 immunology
Abstract

International audience; Human invariant NKT (iNKT) cells are a unique subset of T cells, which recognize glycolipids presented by the CD1d. Among the iNKT cells, several functionally distinct subsets have been characterized according to CD4 and/or CD8 co-receptor expression. The current study is focussed on the CD4(+) iNKT cell subset and its role in an anti-infectious response. We have examined the role of CD4(+) iNKT cells on the intracellular Brucella suis growth. Our results indicate that CD4(+) iNKT cells impair the intramacrophagic growth of Brucella. This inhibition is due to a combination of soluble and contact-dependent mechanisms: IFN-gamma is weakly involved while cytotoxic activities such as the induction of the Fas pathway and the release of lytic granules are major mechanisms. The impairment of Brucella growth by CD4(+) iNKT cells requires an interaction with CD1d on macrophage surface. Also, we have shown that although CD4 regulates several biological responses of CD4(+) iNKT cells, it is not involved in their antibacterial activity. Here, we have shown for the first time that the CD4(+) iNKT cell population has antibacterial activity and thus, participates directly in the elimination of bacteria and/or in the control of bacterial growth by killing infected cells.

Published
2009
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3. The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Author

B. Martoglio, Sébastien Huault, E. Friedmann, Martin Zörnig, F. Guardiola-Serrano, W. S. Wels, Katharina Lückerath, N. Novac, Nathalie Cahuzac, Anne-Odile Hueber, Vladimir Kirkin, Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institute of Biochemistry, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), MerckKGaA, Merck & Co. Inc, and Novartis Institutes for BioMedical Research (NIBR)

Subjects
MESH: ADAM Proteins, Signal peptide, Proteases, MESH: Cell Line, Tumor, Fas Ligand Protein, T-Lymphocytes, Medizin, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Fas ligand, MESH: Protein Structure, Tertiary, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, MESH: RNA, Small Interfering, Disintegrin, MESH: Microscopy, Confocal, Aspartic Acid Endopeptidases, Humans, RNA, Small Interfering, Molecular Biology, Cells, Cultured, 030304 developmental biology, 0303 health sciences, MESH: Humans, Microscopy, Confocal, biology, MESH: Aspartic Endopeptidases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, hemic and immune systems, Cell Biology, Fas receptor, Molecular biology, MESH: Fas Ligand Protein, Transmembrane protein, Protein Structure, Tertiary, Cell biology, ADAM Proteins, MESH: T-Lymphocytes, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, biological phenomena, cell phenomena, and immunity, Intracellular, MESH: Cells, Cultured
Abstract

Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidase-like family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

Published
2007
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4. Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome

Author

Ehl, Anne, Pannicke, Ulrich, Zimmermann, Stefanie-Yvonne, Lorenz, R., Neven, Benedicte, Fuchs, Ilka, Salzer, Ulrich, Speckmann, Carsten, Strauss, Anne, Maass, E., Collet, Benedicte, Enders, Anselm, Favier, Remi, Alessi, Marie-Christine, Rieux-Laucat, Frederic, Zieger, Barbara, Schwarz, Klaus, Ehl, Stephan, Lorenz, Myriam Ricarda, Maaβ, Eberhard, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ALESSI, Marie-Christine

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Somatic cell, Immunology, Fas Ligand Protein, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biochemistry, Germline, Gray platelet syndrome, MESH: Autoimmune Lymphoproliferative Syndrome, MESH: Gray Platelet Syndrome, Correspondence, medicine, MESH: Blood Proteins, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, MESH: Receptors, Cell Surface, MESH: Humans, business.industry, Autoimmune Cytopenia, MESH: Child, Preschool, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, medicine.disease, MESH: Infant, MESH: Male, MESH: Fas Ligand Protein, MESH: Antigens, CD95, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, business, MESH: Female
Abstract

To the editor: The combination of splenomegaly and autoimmune cytopenia is frequently associated with primary immunodeficiencies. The most frequent disease is autoimmune lymphoproliferative syndrome (ALPS), caused by autosomal dominant germline or somatic mutations of the FAS gene.[1][1],[2][2] The

Published
2015

5. Palmitoylation is required for efficient Fas cell death signaling

Author

Sébastien Huault, Hai-Tao He, Krittalak Chakrabandhu, Britta Dost, Zoltán Hérincs, Fabien Conchonaud, Anne-Odile Hueber, Didier Marguet, Ling Peng, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Groupe de chimie organique et matériaux moléculaires (GCOMM), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, MESH: Cell Death, MESH: Cytoskeletal Proteins, MESH: Sequence Homology, Amino Acid, MESH: Membrane Microdomains, Palmitic Acid, MESH: Amino Acid Sequence, Fas ligand, MESH: Protein Structure, Tertiary, Mice, 0302 clinical medicine, MESH: Animals, Cytoskeleton, Internalization, Lipid raft, Caspase, media_common, 0303 health sciences, Cell Death, biology, General Neuroscience, Fas receptor, MESH: Antigens, CD95, Cell biology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Signal transduction, Signal Transduction, Fas Ligand Protein, media_common.quotation_subject, Molecular Sequence Data, macromolecular substances, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Membrane Microdomains, Palmitoylation, MESH: Cytoskeleton, Animals, Humans, Amino Acid Sequence, fas Receptor, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Sequence Homology, Amino Acid, General Immunology and Microbiology, MESH: Fas Ligand Protein, Protein Structure, Tertiary, Cytoskeletal Proteins, biology.protein, MESH: Palmitic Acid
Abstract

Localization of the death receptor Fas to specialized membrane microdomains is crucial to Fas-mediated cell death signaling. Here, we report that the post-translational modification of Fas by palmitoylation at the membrane proximal cysteine residue in the cytoplasmic region is the targeting signal for Fas localization to lipid rafts, as demonstrated in both cell-free and living cell systems. Palmitoylation is required for the redistribution of Fas to actin cytoskeleton-linked rafts upon Fas stimulation and for the raft-dependent, ezrin-mediated cytoskeleton association, which is necessary for the efficient Fas receptor internalization, death-inducing signaling complex assembly and subsequent caspase cascade leading to cell death.

Published
2006
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6. Urinary cytotoxic molecular markers for a noninvasive diagnosis in acute renal transplant rejection*

Author

Sophie Felix, Gérard Rifle, Christophe Ferrand, Jean-Michel Rebibou, Philippe Saas, Jean-Marc Chalopin, Pierre Tiberghien, Maria Yannaraki, Patrick Hervé, Anne Duperrier, Didier Ducloux, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'urologie, andrologie et transplantation rénale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Plateforme de Biomonitoring, Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Saas, Philippe, and Hôpital Saint-Jacques-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Graft Rejection, Male, Nephrology, Pathology, MESH: Membrane Glycoproteins, 030232 urology & nephrology, MESH: Urinary Tract Infections, 030230 surgery, Gastroenterology, Granzymes, MESH: Kidney Transplantation, Postoperative Complications, 0302 clinical medicine, Chronic allograft nephropathy, MESH: Postoperative Complications, MESH: Reverse Transcriptase Polymerase Chain Reaction, Lymphocytes, MESH: Serine Endopeptidases, Kidney transplantation, Kidney, Membrane Glycoproteins, MESH: Middle Aged, MESH: Pore Forming Cytotoxic Proteins, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases, MESH: Tumor Necrosis Factors, Middle Aged, MESH: Predictive Value of Tests, 3. Good health, MESH: Reproducibility of Results, medicine.anatomical_structure, Real-time polymerase chain reaction, Acute Disease, Cytomegalovirus Infections, Tumor Necrosis Factors, Urinary Tract Infections, MESH: Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Pore Forming Cytotoxic Proteins, medicine.medical_specialty, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, Urinary system, MESH: Graft Rejection, Sensitivity and Specificity, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, MESH: Transplantation, Homologous, medicine, Humans, Transplantation, Homologous, RNA, Messenger, MESH: RNA, Messenger, MESH: Granzymes, Transplantation, MESH: Humans, Perforin, business.industry, MESH: Biological Markers, Reproducibility of Results, MESH: Cytomegalovirus Infections, medicine.disease, Kidney Transplantation, MESH: Male, MESH: Sensitivity and Specificity, MESH: Fas Ligand Protein, MESH: Perforin, MESH: Lymphocytes, Complication, business, MESH: Female, Biomarkers
Abstract

International audience; Perforin (P), Granzyme B (GB) and Fas-Ligand (FAS-L) are cytotoxic molecules involved in acute rejection (AR) after renal transplantation. A noninvasive diagnostic test to monitor AR and other complications could improve clinical management. We investigated the predictive and diagnostic interest of target mRNA measurements, with a quantitative PCR assay, in AR, as well as in other clinical complications recurrent in kidney transplantation. One hundred and sixty-two urine specimens from 37 allograft recipients were investigated. Clinical settings were AR, urinary tract infection (UTI), cytomegalovirus infection (CMVi) or disease (CMVd), chronic allograft nephropathy (CAN), delayed graft function (DGF) and stable graft course (controls). In the case of AR, mRNA levels of all three molecules were significantly higher than in recipients not showing any clinically evident signs of complication. Indeed, it was observed that expression levels of P, GB and Fas-L mRNA also increase in other clinical situations such as UTI, CMV and DGF. Finally, kinetic studies in three patients with AR revealed that increased P, GB and Fas-L mRNA levels could precede or were concomitant with increased serum creatinin levels. P, GB and Fas-L gene expression in urine specimens were upregulated in AR episodes but also in UTI, CMV infection and DGF. Therefore, this technique would appear to be of limited clinical value as a noninvasive method of diagnosing AR.

Published
2006
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7. EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1: role of NF- B, STAT1, and p53

Author

Georg W. Bornkamm, Jean Feuillard, Ibtissam Youlyouz-Marfak, Christophe Le Clorennec, Eric Adriaenssens, Jean Coll, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, and Université de Limoges (UNILIM)

Subjects
MESH: Signal Transduction, Epstein-Barr Virus Infections, Herpesvirus 4, Human, MESH: I-kappa B Proteins, T-Lymphocytes, MESH: Membrane Glycoproteins, MESH: NF-kappa B, Apoptosis, MESH: Estrogens, Biochemistry, chemistry.chemical_compound, NF-KappaB Inhibitor alpha, MESH: Genetic Vectors, hemic and lymphatic diseases, MESH: Animals, MESH: Interferon-Stimulated Gene Factor 3, STAT1, MESH: Tumor Suppressor Protein p53, Genes, Dominant, B-Lymphocytes, Membrane Glycoproteins, MESH: Epstein-Barr Virus Infections, biology, NF-kappa B, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, hemic and immune systems, MESH: Tumor Necrosis Factors, Interferon-Stimulated Gene Factor 3, Hematology, Transfection, Fas receptor, MESH: Gene Expression Regulation, MESH: Antigens, CD95, Cell biology, MESH: Cell Transformation, Viral, Tumor Necrosis Factors, I-kappa B Proteins, MESH: Epstein-Barr Virus Nuclear Antigens, Plasmids, Signal Transduction, MESH: Mutation, MESH: Cell Line, Tumor, Fas Ligand Protein, Genetic Vectors, Immunology, Virus, Viral Matrix Proteins, Viral Proteins, Immune system, MESH: Plasmids, MESH: B-Lymphocytes, Cell Line, Tumor, otorhinolaryngologic diseases, Animals, Humans, fas Receptor, MESH: Viral Matrix Proteins, MESH: Humans, MESH: Apoptosis, MESH: Herpesvirus 4, Human, Estrogens, NF-κB, Cell Biology, Cell Transformation, Viral, MESH: Viral Proteins, MESH: Fas Ligand Protein, IκBα, MESH: T-Lymphocytes, Epstein-Barr Virus Nuclear Antigens, Gene Expression Regulation, chemistry, Mutation, biology.protein, Cancer research, Tumor Suppressor Protein p53, MESH: Genes, Dominant
Abstract

Epstein-Barr virus (EBV) induces CD95 expression and the CD95 gene (FAS) is regulated by NF-kappaB, STAT1, and/or p53. To understand the contribution of these factors in the regulation of CD95 by EBV in lymphoblastoid cell lines (LCLs), we cloned dominant-active IkappaBalpha, active (STAT1alpha) and inactive (STAT1beta) forms of STAT1, p53, a dominant-negative mutant of LMP1, and wild-type LMP1 into a novel double-inducible episomal vector, pRT-1. These plasmids were stably transfected either into wild-type LCLs or EREB2-5 cells, an LCL with an estrogen-regulatable EBNA2 protein. Inhibition of LMP1 signaling decreased expression of CD95, whereas overexpression of LMP1 markedly increased it. Induction of the latency III program in EREB2-5 cells correlated with activation of NF-kappaB, STAT1, and p53. CD95 expression was regulated by these 3 transcriptional systems. STAT1 and p53 activation were secondary to NF-kappaB activation. CD95 surface expression sensitized EBV-infected B cells to the induction of CD95-mediated apoptosis. In vitro inhibition of CD95-CD95 ligand interaction was found to reverse T-cell killing of EBV-infected B cells. Therefore, LMP1 activation of NF-kappaB sensitizes infected B cells to CD95-mediated apoptosis and renders EBV latency III-immortalized B cells susceptible to elimination by the immune system, contributing to the establishment of a host/virus equilibrium.

Published
2006
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8. Expression of a dominant negative form of Daxxin vivo rescues motoneurons from Fas (CD95)-induced cell death

Author

David C. Hancock, Catherine Barthélémy, Brigitte Pettmann, Arnaud Couzinet, Anne-Odile Hueber, Cédric Raoul, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Développement et pathologie du motoneurone, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Lincoln's Inn Fields Laboratories, Cancer Research UK, and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Indoles, Time Factors, MESH: Membrane Glycoproteins, Fluorescent Antibody Technique, MESH: Nitric Oxide Synthase Type I, Apoptosis, Cell Count, Nitric Oxide Synthase Type I, MESH: Spinal Cord, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Transcriptional regulation, MESH: Animals, MESH: Nerve Tissue Proteins, FADD, MESH: In Situ Nick-End Labeling, MESH: Fluorescent Antibody Technique, Genes, Dominant, MESH: Indoles, Motor Neurons, 0303 health sciences, Membrane Glycoproteins, biology, MESH: Peptides, Reverse Transcriptase Polymerase Chain Reaction, General Neuroscience, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Fas receptor, MESH: Antigens, CD95, Cell biology, Spinal Cord, MESH: Nitric Oxide Synthase, Co-Repressor Proteins, Oligopeptides, MESH: Motor Neurons, Genetically modified mouse, Programmed cell death, Fas Ligand Protein, MESH: Mice, Transgenic, Transgene, Green Fluorescent Proteins, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Green Fluorescent Proteins, Death-associated protein 6, MESH: Mice, Inbred C57BL, MESH: Intracellular Signaling Peptides and Proteins, In Situ Nick-End Labeling, Animals, RNA, Messenger, fas Receptor, MESH: Mice, MESH: Adaptor Proteins, Signal Transducing, MESH: RNA, Messenger, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Cell Count, MESH: Apoptosis, MESH: Time Factors, MESH: Embryo, Mammalian, JNK Mitogen-Activated Protein Kinases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: JNK Mitogen-Activated Protein Kinases, Embryo, Mammalian, MESH: Fas Ligand Protein, Mice, Inbred C57BL, nervous system, biology.protein, Nitric Oxide Synthase, MESH: Genes, Dominant, Carrier Proteins, Peptides, MESH: Nuclear Proteins, 030217 neurology & neurosurgery, Molecular Chaperones
Abstract

International audience; Fas-induced death of motoneurons in vitro has been shown to involve two signaling cascades that act together to execute the death program: a Fas-Daxx-ASK-1-p38 kinase-nNOS branch, which controls transcriptional and post-translational events, and the second classical Fas-FADD-caspase-8 branch. To analyze the role of Daxx in the developmental motoneuron cell death, we studied Fas-dependent cell death in motoneurons from transgenic mice that overexpress a dominant-negative form of Daxx. Motoneurons purified from these transgenic mice are resistant to Fas-induced death. This protective effect is specific to Fas because ultraviolet irradiation-triggered death is not affected by the transgene. The Daxx and the FADD pathways work in parallel because only Daxx, but not FADD, is involved in the transcriptional control of neuronal nitric oxide synthase and nitric oxide production. Nevertheless, we do not observe involvement of Daxx in developmental motoneuronal cell death, as the pattern of naturally occurring programmed cell death in vivo is normal in transgenic mice overexpressing the dominant negative form of Daxx, suggesting that Daxx-independent pathways are used during development.

Published
2004
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9. Targeting c-FLIP in cancer

Author

Olivier Micheau, Sarah Shirley, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, INCa (Polynom174), ANR-06-JCJC-0103,TRAILCHIM,TRAIL et chimiothérapies anticancéreuses(2006), European Project, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), ANR-06-JCJC-0103, ANR--07-PCV-0031,ANR-06-JCJC-0103, ANR--07-PCV-0031, Micheau, Olivier, Programme 'Jeunes chercheuses et jeunes chercheurs' - TRAIL et chimiothérapies anticancéreuses - - TRAILCHIM2006 - ANR-06-JCJC-0103 - JCJC - VALID, Apoptrain, Marie Curie RTN - INCOMING, and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)

Subjects
Cancer Research, MESH: CASP8 and FADD-Like Apoptosis Regulating Protein, Transcription, Genetic, Regulator, CASP8 and FADD-Like Apoptosis Regulating Protein, Apoptosis, MESH : Fas Ligand Protein, MESH : RNA, Small Interfering, Ligands, MESH : TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand, 0302 clinical medicine, Neoplasms, MESH: RNA, Small Interfering, MESH: Ligands, MESH: Neoplasms, RNA, Small Interfering, Death Receptors, Cancer, Regulation of gene expression, 0303 health sciences, MESH : Ligands, MESH: Gene Expression Regulation, Neoplastic, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, MESH : Antineoplastic Agents, Oncology, 030220 oncology & carcinogenesis, Death-inducing signaling complex, MESH: TNF-Related Apoptosis-Inducing Ligand, Programmed cell death, Fas Ligand Protein, c-FLIP, MESH : Gene Expression Regulation, Neoplastic, Antineoplastic Agents, Biology, 03 medical and health sciences, Downregulation and upregulation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH : Protein Processing, Post-Translational, MESH: Humans, MESH: Apoptosis, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, MESH : CASP8 and FADD-Like Apoptosis Regulating Protein, MESH : Neoplasms, MESH: Fas Ligand Protein, Flip, MESH: Protein Processing, Post-Translational, Cancer cell, MESH: Antineoplastic Agents, Protein Processing, Post-Translational, MESH : Apoptosis
Abstract

International audience; Cellular-FLICE inhibitory protein (c-FLIP) is a key anti-apoptotic regulator that inhibits cell death mediated by the death receptors Fas, DR4, DR5, and TNF-R1. Three splice variants of c-FLIP function at the DISC level by blocking the processing and activation of procaspase-8 and -10. Overexpression of c-FLIP has been identified in many different tumour types, and its downregulation in vitro has been shown to restore apoptosis mediated by CD95L and TRAIL. c-FLIP therefore represents a promising target for cancer therapy. This review focuses on the molecular mechanisms that control c-FLIP expression and current research into inhibitors of the protein. Increasing evidence supports the investigation of c-FLIP as a therapeutic target to restore an apoptotic response in cancer cells.

Published
2013
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10. EVER2 protein binds TRADD to promote TNF-α-induced apoptosis

Author

Guillaume Gaud, D Guillemot, Yves Jacob, Michel Favre, Françoise Vuillier, Génétique, Papillomavirus et Cancer Humain, Institut Pasteur [Paris] (IP), This work was supported by grants from the ANR (contract no. 026 01), ARC (contract no. A09/1/5031) and the Ligue Nationale contre le Cancer (contract no. RS07/75-75) and by a donation from ODYSSE RE Holdings Corp. G GAUD was supported by a fellowship from the ANR (contract no. 026 01)., We also thank Alex Edelman and Associates for correcting the English version of the manuscript., and Institut Pasteur [Paris]

Subjects
Cancer Research, MESH: TNF Receptor-Associated Factor 2, MESH: NF-kappa B, MESH: Caspase 8, Inhibitor of Apoptosis Proteins, polymorphism, TNF-Related Apoptosis-Inducing Ligand, MESH: Recombinant Proteins, Jurkat Cells, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Jurkat Cells, MESH: TNF Receptor-Associated Death Domain Protein, 0303 health sciences, Caspase 8, NF-kappa B, apoptosis, Recombinant Proteins, TNF Receptor-Associated Death Domain Protein, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Receptor-Interacting Protein Serine-Threonine Kinases, MESH: HEK293 Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, RNA Interference, Original Article, MESH: Membrane Proteins, Signal transduction, MESH: TNF-Related Apoptosis-Inducing Ligand, Protein Binding, Programmed cell death, Fas Ligand Protein, Immunology, MESH: RNA Interference, EVER2, MESH: Receptor-Interacting Protein Serine-Threonine Kinases, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, RIPK1, Humans, MESH: Protein Binding, Alleles, 030304 developmental biology, MESH: Humans, Tumor Necrosis Factor-alpha, MESH: Alleles, MESH: Apoptosis, MESH: Inhibitor of Apoptosis Proteins, Membrane Proteins, Cell Biology, TNF Receptor-Associated Factor 2, TRADD, MESH: Fas Ligand Protein, Protein Structure, Tertiary, MicroRNAs, HEK293 Cells, Apoptosis, MESH: Tumor Necrosis Factor-alpha, Cancer research, TMC8, MESH: MicroRNAs
Abstract

International audience; EVER1 and 2 confer resistance to cutaneous oncogenic human papillomavirus infections by downregulating the activating protein 1 (AP-1) signaling pathway. Defects in their expression are associated with susceptibility to epidermodysplasia verruciformis, which is characterized by persistent β-HPV infection, tumor necrosis factor alpha (TNF-α) overproduction in keratinocytes and the development of skin cancers. TNF-α-induced apoptosis is a key defense strategy, preventing the persistence of the virus within cells, but the role of EVER proteins in this cell death mechanism triggered by extrinsic stimuli is unknown. We show here that EVER2 induces TNF-α- and TRAIL-dependant apoptosis. It interacts with the N-terminal domain of TRADD, impairs the recruitment of TRAF2 and RIPK1 and promotes apoptosis. The skin cancer-associated EVER2 I306 allele results in an impaired TRADD-EVER2 interaction, with lower levels of cell death following treatment with TNF-α. These data highlight a new, critical function of EVER2 in controlling cell survival in response to death stimuli.

Published
2013
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11. Functional characterization of a chimeric soluble Fas ligand polymer with in vivo anti-tumor activity

Author

Mike Maillasson, Delphine Lapaillerie, Patrick Legembre, Aurore Morello, Jean-Luc Taupin, Laure Garrigue-Antar, Sophie Daburon, Marc Bonneu, Myriam Capone, Pierre Costet, Julie Déchanet-Merville, Jean-François Moreau, Christel Devaud, Nathalie Hargous, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Animalerie spécialisée, Université Bordeaux Segalen - Bordeaux 2, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre génomique fonctionnelle, Récepteur de mort et échappement tumoral, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Anatomy and Physiology, Mouse, Oncogene Proteins, Fusion, lcsh:Medicine, Apoptosis, Leukemia inhibitory factor receptor, Ligands, Biochemistry, Fas ligand, Jurkat Cells, Mice, 0302 clinical medicine, MESH: Genetic Vectors, Immune Physiology, Neoplasms, Molecular Cell Biology, Basic Cancer Research, MESH: Jurkat Cells, MESH: Ligands, MESH: Animals, MESH: Neoplasms, lcsh:Science, Receptor, 0303 health sciences, Immune System Proteins, Multidisciplinary, Cell Death, hemic and immune systems, Animal Models, Fas receptor, Recombinant Proteins, Cell biology, MESH: Antigens, CD95, Oncology, 030220 oncology & carcinogenesis, Cytokines, Medicine, biological phenomena, cell phenomena, and immunity, Research Article, Fas Ligand Protein, Receptors, OSM-LIF, Recombinant Fusion Proteins, Genetic Vectors, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Transfection, 03 medical and health sciences, Chimera (genetics), Model Organisms, Cell surface receptor, MESH: Recombinant Fusion Proteins, Animals, Humans, fas Receptor, MESH: Mice, 030304 developmental biology, Receptor Aggregation, MESH: Receptors, OSM-LIF, MESH: Humans, MESH: Transfection, MESH: Apoptosis, lcsh:R, Proteins, MESH: Fas Ligand Protein, lcsh:Q, MESH: Oncogene Proteins, Fusion
Abstract

International audience; Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.

Published
2013
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12. TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

Author

Muhammad Imran Arshad, Sabrina Nabti, Annie L'Helgoualc'h, Michel Rauch, Claire Piquet-Pellorce, Christian Trautwein, Frédéric Ezan, Michel Samson, Agnès Lehuen, Francisco Javier Cubero, Catherine Lucas-Clerc, Jean-Philippe Girard, Solène Patrat-Delon, Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Medical Department III, University Hospital Aachen, Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : RNA, Messenger, medicine.medical_treatment, Gene Expression, Galactosamine, MESH : Hepatocytes, Hepatitis, Animal, MESH : Fas Ligand Protein, Fas ligand, MESH: Antibodies, Monoclonal, TNF-Related Apoptosis-Inducing Ligand, MESH: Hepatocytes, MESH : TNF-Related Apoptosis-Inducing Ligand, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, MESH : Receptors, Tumor Necrosis Factor, Type I, MESH: Receptors, Tumor Necrosis Factor, Type II, Concanavalin A, MESH: Animals, MESH : Acute Lung Injury, MESH: Galactosamine, MESH : Concanavalin A, Liver injury, MESH: Receptors, Tumor Necrosis Factor, Type I, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, biology, MESH: Hepatitis, Animal, Antibodies, Monoclonal, Interleukin, MESH : Receptors, Tumor Necrosis Factor, Type II, Natural killer T cell, 3. Good health, Cytokine, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Tumor necrosis factor alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: TNF-Related Apoptosis-Inducing Ligand, Fas Ligand Protein, MESH: Gene Expression, MESH: Interleukins, Acute Lung Injury, Primary Cell Culture, chemical and pharmacologic phenomena, MESH: Concanavalin A, MESH: Primary Cell Culture, 03 medical and health sciences, MESH : Mice, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, RNA, Messenger, MESH : Perforin, MESH : Primary Cell Culture, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Hepatitis, Hepatology, MESH : Galactosamine, Perforin, Tumor Necrosis Factor-alpha, Interleukins, MESH: Acute Lung Injury, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Interleukin-33, medicine.disease, MESH : Natural Killer T-Cells, MESH: Fas Ligand Protein, MESH: Perforin, MESH : Gene Expression, MESH: Natural Killer T-Cells, MESH: Tumor Necrosis Factor-alpha, Immunology, Hepatocytes, biology.protein, Cancer research, Natural Killer T-Cells, MESH : Animals, MESH : Interleukins, MESH : Hepatitis, Animal
Abstract

International audience; UNLABELLED: Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin(-/-) , tumor necrosis factor related apoptosis inducing ligand (TRAIL)(-/-) , and NKT cell-deficient (CD1d(-/-) ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. CONCLUSION: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα.

Published
2012
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13. NK cells are strongly activated by Lassa and Mopeia virus-infected human macrophages in vitro but do not mediate virus suppression

Author

Russier, Marion, Reynard, Stéphanie, Tordo, Noël, Baize, Sylvain, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)

Subjects
Gene Expression Regulation, Viral, MESH: Killer Cells, Natural, Fas Ligand Protein, MESH: Interferon-gamma, [SDV]Life Sciences [q-bio], MESH: Vero Cells, Cell Growth Processes, MESH: Lassa Fever, Lymphocyte Activation, Granzymes, Statistics, Nonparametric, TNF-Related Apoptosis-Inducing Ligand, MESH: Coculture Techniques, Interferon-gamma, MESH: Gene Expression Regulation, Viral, Lassa Fever, MESH: RNA, MESH: Reverse Transcriptase Polymerase Chain Reaction, Chlorocebus aethiops, Animals, Humans, MESH: Animals, Lassa virus, MESH: Lymphocyte Activation, Vero Cells, MESH: Granzymes, MESH: Statistics, Nonparametric, MESH: K562 Cells, MESH: Humans, Reverse Transcriptase Polymerase Chain Reaction, Macrophages, MESH: Lassa virus, MESH: Macrophages, MESH: Cercopithecus aethiops, Coculture Techniques, MESH: Fas Ligand Protein, Killer Cells, Natural, MESH: Cell Growth Processes, RNA, K562 Cells, MESH: TNF-Related Apoptosis-Inducing Ligand
Abstract

International audience; Lassa virus (LASV) and Mopeia virus (MOPV) are closely related Arenaviruses. LASV causes hemorrhagic fever, whereas MOPV is not pathogenic. Both viruses display tropism for APCs such as DCs and macrophages. During viral infections, NK cells are involved in the clearance of infected cells and promote optimal immune responses by interacting with APCs. We used an in vitro model of human NK and APC coculture to study the role of NK cells and to characterize their interactions with APCs during LASV and MOPV infections. As expected, NK cells alone were neither infected nor activated by LASV and MOPV, and infected DCs did not activate NK cells. By contrast, LASV- and MOPV-infected macrophages activated NK cells, as shown by the upregulation of CD69, NKp30, and NKp44, the downregulation of CXCR3, and an increase in NK-cell proliferation. NK cells acquired enhanced cytotoxicity, as illustrated by the increase in granzyme B (GrzB) expression and killing of K562 targets, but did not produce IFN-γ. Contact between NK cells and infected macrophages and type I IFNs were essential for activation; however, NK cells could not kill infected cells and control infection. Overall, these findings show that MOPV- as well as pathogenic LASV-infected macrophages mediate NK-cell activation.

Published
2012
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14. Imatinib sensitizes T-cell lymphocytes from chronic myeloid leukemia patients to FasL-induced cell death: a brief communication

Author

Emmanuelle Stebe, Philippe Rousselot, Delphine Rea, Jill Patrice Cassuto, Anne-Odile Hueber, Francois-Xavier Mahon, Laurence Legros, Nathalie Ebran, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Service d'Hématologie Clinique, Hôpital l'Archet, Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, and Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Cancer Research, Lymphocyte, MESH: Piperazines, Apoptosis, MESH: Flow Cytometry, Cell Separation, Lymphocyte Activation, Fas ligand, Piperazines, 0302 clinical medicine, MESH: Aged, 80 and over, hemic and lymphatic diseases, Immunology and Allergy, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Myeloid leukemia, Middle Aged, Fas receptor, Flow Cytometry, 3. Good health, MESH: Antigens, CD95, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Benzamides, Imatinib Mesylate, Female, medicine.drug, Adult, Fas Ligand Protein, T cell, Immunology, Antineoplastic Agents, chemical and pharmacologic phenomena, Biology, MESH: Cell Separation, MESH: Lymphopenia, 03 medical and health sciences, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Lymphopenia, medicine, Humans, fas Receptor, MESH: Lymphocyte Activation, 030304 developmental biology, Aged, Pharmacology, MESH: Humans, MESH: Apoptosis, Imatinib, MESH: Adult, medicine.disease, MESH: Male, MESH: Fas Ligand Protein, Imatinib mesylate, Pyrimidines, MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive, MESH: Pyrimidines, MESH: Antineoplastic Agents, MESH: Female
Abstract

International audience; There is now substantial evidence that imatinib may affect immune responses, especially those mediated by T lymphocytes. Fas (CD95/Apo-1), a cell death receptor, is a key regulator of the immune system. We have explored the consequences of treatment on the Fas system in chronic myeloid leukemia patients treated with imatinib. In comparison with healthy controls, we found not only a mild blood lymphopenia but also impairment of phytohemagglutinin activation in CD4Fas and CD8Fas lymphocytes of imatinib-treated patients. Moreover, these lymphocyte populations were more sensitive to FasL-induced cell death in relation to an increase in Fas expression at the cell surface. Taken together, these results reveal the role of Fas receptor in the lymphopenia observed in patients treated with imatinib, with potential deleterious consequences on antileukemic responses against this immunogenic hematological malignancy.

Published
2012
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15. CD95 triggers Orai1-mediated localized Ca2+ entry, regulates recruitment of protein kinase C (PKC) β2, and prevents death-inducing signaling complex formation

Author

Anne-Marie Vacher, Patrick Legembre, Bruno Ségui, Laurence Bresson-Bepoldin, Benjamin Chaigne-Delalande, Pierre Vacher, Thierry Levade, Thomas Ducret, Josy Reiffers, Jean-François Moreau, Nadine Khadra, Aubin Penna, Michael D. Cahalan, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Validation et identification de nouvelles cibles en oncologie (VINCO), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, Department of Physiology and Biophysics and Center for Immunology, University of California [Irvine] (UCI), University of California-University of California, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Agence Nationale de la Recherche (ANR JC07_183182), Institut National du Cancer (Projets Libres Recherche Biomédicale), Cancéropole Grand Ouest, Région Bretagne, Rennes Métropole, Université de Rennes-1, Ligue Contre le Cancer (Comités d'Ille-et-Vilaine/du Morbihan/des Côtes d'Armor/du Maine et Loire/des Landes), and the National Institutes of Health (Grant NS-14609, to M.D.C.). N.K. is supported by Region Bretagne (Allocation de Recherche Doctorale)., Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Université de Rennes (UR), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé

Subjects
Caspase complex, Protein Kinase C beta, MESH: Flow Cytometry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Caspase 8, 03 medical and health sciences, 0302 clinical medicine, MESH: Microscopy, Confocal, MESH: Blotting, Western, FADD, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Protein kinase C, 030304 developmental biology, Death domain, 0303 health sciences, MESH: Statistics, Nonparametric, MESH: Caspase 10, Multidisciplinary, MESH: Humans, biology, MESH: Immunoprecipitation, MESH: Apoptosis, STIM1, MESH: Multiprotein Complexes, MESH: Fas-Associated Death Domain Protein, MESH: Protein Kinase C, MESH: Fas Ligand Protein, Cell biology, MESH: Antigens, CD95, MESH: Cell Line, 030220 oncology & carcinogenesis, MESH: Calcium, Death-inducing signaling complex, biology.protein, MESH: Calcium Channels, Caspase 10
Abstract

The death receptor CD95 plays a pivotal role in immune surveillance and immune tolerance. Binding of CD95L to CD95 leads to recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates caspase-8 and caspase-10. Efficient formation of the CD95/FADD/caspase complex, known as the death-inducing signaling complex (DISC), culminates in the induction of apoptosis. We show that cells exposed to CD95L undergo a reorganization of the plasma membrane in which the Ca 2+ release-activated Ca 2+ channel Orai1 and the endoplasmic reticulum-resident activator stromal interaction molecule 1 colocalize with CD95 into a micrometer-sized cluster in which the channel elicits a polarized entry of calcium. Orai1 knockdown and expression of a dominant negative construct (Orai1E106A) reveal that on CD95 engagement, the Orai1-driven localized Ca 2+ influx is fundamental to recruiting the Ca 2+ -dependent protein kinase C (PKC) β2 to the DISC. PKCβ2 in turn transiently holds the complex in an inactive status, preventing caspase activation and transmission of the apoptotic signal. This study identifies a biological role of Ca 2+ and the Orai1 channel that drives a transient negative feedback loop, introducing a lag phase in the early steps of the CD95 signal. We suggest that these localized events provide a time of decision to prevent accidental cell death.

Published
2011
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16. S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells

Author

Cindy Godard, Patrick Legembre, Selvakumar Subramaniam, Olivier Cauvard, Ali Bettaieb, Lissbeth Leon-Bollotte, Antonio Martinez–Ruiz, Jean-François Jeannin, Stéphanie Plenchette–Colas, Catherine Paul, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Servicio de Immunologia, Hospital Universitario de la Princesa-Instituto de Investigacion Sanitaria Princesa, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ligue Nationale Contre le Cancer (Comités de Sâone-et-Loire, de Nevers, de Côte d'Or, et le Cancéropole Grand Est), le gouvernement espagnol (grant CSD007-00020), Association pour la Recherche Contre le Cancer (L.L-B.), Institut National du Cancer (L.L-B.), la Région de Bourgogne (S.S.), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Hospital Universitario de La Princesa-Instituto de Investigacion Sanitaria del Hospital de la Princesa, Hospital Universitario de La Princesa, and Université de Rennes (UR)

Subjects
MESH: Nitroglycerin, MESH: Signal Transduction, Time Factors, MESH: Membrane Microdomains, Apoptosis, MESH : Fas Ligand Protein, Cytoplasmic part, MESH: Lipid A, Fas ligand, Mice, Nitroglycerin, 0302 clinical medicine, MESH : Protein Transport, MESH : Female, MESH: Animals, FADD, Lipid raft, 0303 health sciences, Tumor, biology, Colon Cancer, MESH : Lipid A, MESH : Biotinylation, Gastroenterology, Fas receptor, MESH: Antigens, CD95, Protein Transport, Lipid A, MESH : Colonic Neoplasms, MESH : Nitric Oxide, MESH : Nitric Oxide Donors, 030220 oncology & carcinogenesis, Colonic Neoplasms, Death-inducing signaling complex, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Mutation, MESH : Transfection, Signal Transduction, MESH : Time Factors, MESH: Protein Transport, Fas Ligand Protein, MESH : Mammary Neoplasms, Experimental, MESH: Mutation, MESH: Cell Line, Tumor, MESH: Mammary Neoplasms, Experimental, Nitric Oxide, Transfection, Caspase 8, 03 medical and health sciences, Membrane Microdomains, Cell Line, Tumor, MESH : Mice, Animals, Humans, Biotinylation, Nitric Oxide Donors, MESH: Biotinylation, Cysteine, fas Receptor, MESH: Mice, MESH : Protein Processing, Post-Translational, 030304 developmental biology, MESH : Signal Transduction, MESH: Colonic Neoplasms, MESH : Cysteine, MESH: Humans, Hepatology, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH: Transfection, MESH : Humans, MESH: Time Factors, Mammary Neoplasms, Experimental, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cysteine, MESH: Nitric Oxide Donors, Molecular biology, Signaling, MESH: Fas Ligand Protein, MESH : Nitroglycerin, Localization, MESH: Nitric Oxide, MESH: Protein Processing, Post-Translational, Mutation, biology.protein, MESH : Membrane Microdomains, MESH : Animals, MESH : Antigens, CD95, Protein Processing, Post-Translational, MESH: Female, MESH : Apoptosis
Abstract

International audience; BACKGROUND & AIMS: Fas belongs to the family of tumor necrosis factor receptors which induce apoptosis. Many cancer cells express Fas but do not undergo Fas-mediated apoptosis. Nitric oxide reverses this resistance by increasing levels of Fas at the plasma membrane. We studied the mechanisms by which NO affects Fas function. METHODS: Colon and mammary cancer cell lines were incubated with the NO donor glyceryl trinitrate or lipid A; S-nitrosylation of Fas was monitored using the biotin switch assay. Fas constructs that contained mutations at cysteine residues that prevent S-nitrosylation were used to investigate the involvement of S-nitrosylation in Fas-mediated cell death. Apoptosis was monitored according to morphologic criteria. RESULTS: NO induced S-nitrosylation of cysteine residues 199 and 304 in the cytoplasmic part of Fas. In cancer cells that overexpressed wild-type Fas, S-nitrosylation induced Fas recruitment to lipid rafts and sensitized the cells to Fas ligand. In cells that expressed a mutant form of Fas in which cysteine 304 was replaced by valine residue, NO-mediated translocation of Fas to lipid rafts was affected and the death-inducing signal complex and synergistic effect of glyceryl trinitrate-Fas ligand were inhibited significantly. These effects were not observed in cells that expressed Fas with a mutation at cysteine 199. CONCLUSIONS: We identified post-translational modifications (S-nitrosylation of cysteine residues 199 and 304) in the cytoplasmic domain of Fas. S-nitrosylation at cysteine 304 promotes redistribution of Fas to lipid rafts, formation of the death-inducing signal complex, and induction of cell death.

Published
2011
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17. The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway

Author

Cécile Contin-Bordes, Sophie Daburon, Patrick Blanco, Nadine Khadra, Laurent Counillon, Thomas Ducret, Patrick Legembre, Pierre Vacher, Jacques Le Seyec, Sébastien Tauzin, Jean-François Moreau, Eric Selva, Paul Hofman, Benjamin Chaigne-Delalande, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Infection bactérienne, inflammation, et carcinogenèse digestive, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources Biologiques-Tumorothèque, Centre Hospitalier Universitaire de Nice (CHU Nice), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa (projets libres recherche biomédicale), Cancéropole GO, Région Bretagne, Rennes Métropole, Université de Rennes-1, Ligue Contre le Cancer (Comités d'Ille-et-Vilaine/Morbihan/Côtes d'Armor/Maine et Loire), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Nice Sophia Antipolis (... - 2019) (UNS), and Brébion, Alice

Subjects
MESH: Signal Transduction, Apoptosis, Autoimmunity, Phosphatidylinositol 3-Kinases, Cell Movement, MESH: Transendothelial and Transepithelial Migration, Molecular Cell Biology, Lupus Erythematosus, Systemic, Signaling in Cellular Processes, Membrane Receptor Signaling, Pseudopodia, Biology (General), Receptor, MESH: Cell Movement, 0303 health sciences, Cell Death, T Cells, General Neuroscience, 030302 biochemistry & molecular biology, Cell Migration Pathway, Cell migration, Fas receptor, 3. Good health, Cell biology, MESH: Antigens, CD95, src-Family Kinases, MESH: HEK293 Cells, Signal transduction, General Agricultural and Biological Sciences, Research Article, Signal Transduction, Fas Ligand Protein, QH301-705.5, Immune Cells, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, MESH: Lupus Erythematosus, Systemic, fas Receptor, PI3K/AKT/mTOR pathway, 030304 developmental biology, MESH: Humans, General Immunology and Microbiology, MESH: Apoptosis, HEK 293 cells, Transendothelial and Transepithelial Migration, Correction, MESH: Fas Ligand Protein, HEK293 Cells, MESH: src-Family Kinases, MESH: Phosphatidylinositol 3-Kinases, MESH: Pseudopodia
Abstract

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells., Author Summary The “death receptor” CD95 (also known as Fas) plays an essential role in ensuring immune tolerance of self antigens as well as in the elimination of the body's cells that have been infected or transformed. This receptor is engaged by the membrane-bound ligand CD95L, which can be released into blood circulation after cleavage by metalloproteases. Hitherto, most of the studies on the CD95 signal have been performed with chimeric CD95Ls that mimic the membrane-bound ligand and exhibit a level of aggregation beyond that described for the metalloprotease-cleaved ligand. Multi-aggregated CD95L elicits a caspase-driven apoptotic signal. In this study, we observe that levels of soluble and naturally processed CD95L in sera of patients suffering from lupus correlate with disease severity. Strikingly, although this soluble CD95L fails to trigger cell death unlike its chimeric version, it induces a “non-canonical” Ca2+/c-yes/PI3K-dependent signaling pathway that promotes the transmigration of T-lymphocytes across the endothelial barrier. These findings shed light on an entirely new role for the soluble CD95L that may contribute to local or systemic tissue damage by enhancing the infiltration of activated T-lymphocytes. Overall, these findings underline the importance of revisiting the role of this “apoptotic cytokine” in the context of chronic inflammatory disorders.

Published
2011
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18. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions

Author

Marie de Tayrac, Tony Avril, Jean Mosser, Anne Jary, Elodie Vauleon, Stephan Saikali, Véronique Quillien, Abderrahmane Hamlat, Service de Biologie, CRLCC Eugène Marquis (CRLCC), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], De Villemeur, Hervé, and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cytotoxicity, Immunologic, MESH: Neoplasm Proteins, medicine.medical_treatment, T-Lymphocytes, Cell, MESH: Antigens, Neoplasm, MESH: Flow Cytometry, Lymphocyte proliferation, B7-H1 Antigen, MESH: Histocompatibility Antigens Class I, 0302 clinical medicine, MESH: Lectins, HLA Antigens, Lectins, MESH: HLA-A2 Antigen, MESH: Transforming Growth Factor beta2, Immunology and Allergy, MESH: Antigens, CD, MESH: HLA Antigens, Oligonucleotide Array Sequence Analysis, 0303 health sciences, MESH: Glioblastoma, Flow Cytometry, MESH: Gene Expression Regulation, 3. Good health, Cell biology, Neoplasm Proteins, medicine.anatomical_structure, Neurology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Fas Ligand Protein, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon-gamma, T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Interferon-gamma, Transforming Growth Factor beta2, MESH: Gene Expression Profiling, Immune system, MART-1 Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Antigens, Neoplasm, Glioma, Cell Line, Tumor, MESH: Cell Proliferation, HLA-A2 Antigen, MESH: Indoleamine-Pyrrole 2,3,-Dioxygenase, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, RNA, Messenger, MESH: Cytotoxicity, Immunologic, 030304 developmental biology, Cell Proliferation, MESH: RNA, Messenger, HLA-G Antigens, MESH: Humans, Gene Expression Profiling, Histocompatibility Antigens Class I, Immunotherapy, medicine.disease, MESH: Fas Ligand Protein, MESH: T-Lymphocytes, Gene Expression Regulation, Cell culture, MESH: Oligonucleotide Array Sequence Analysis, Cancer research, Neurology (clinical), Glioblastoma
Abstract

International audience; Immunotherapy is a promising new treatment for patients suffering from glioma, in particular glioblastoma multiforme (GBM). However, tumour cells use different mechanisms to escape the immune responses induced by the treatment. As many other tumours, gliomas express or secrete several immunosuppressive molecules that regulate immune cell functions. In this study, we first analysed FasL, HLA-G, IDO, PDL-1 and TGF-beta1, -beta2 and -beta3 expression by transcriptomic microarray analysis in a series of 20 GBM samples and found respectively 15%, 60%, 85%, 30%, 70%, 80% and 35% of positive specimens. mRNA expression was then confirmed in 10 GBM primary cell lines and 2 immortalised cell lines U251 and U87MG. Furthermore, the protein expression of PDL-1, IDO activity and TGF-beta2 secretion were found on most of the untreated GBM primary cell lines. Remarkably, treatment with IFN-gamma increased the PDL-1 cell surface expression and the IDO activity, but reduced the TGF-beta2 secretion of GBM cell lines. We finally analysed the immunosuppressive effects of IDO, PDL-1 and TGF-beta1-3 by measuring IFN-gamma production and cell cytotoxicity activity of tumour antigen-specific T cells. PDL-1 partially affected the IFN-gamma production of antigen-specific T cells in response to GBM primary cell lines, and IDO inhibited lymphocyte proliferation induced by lectins. None of these molecules directly affected the T cell cytotoxicity function. Due to the functional role of PDL-1 and IDO molecules expressed by GBM cells, one could expect that blocking these molecules in the immunotherapy strategies would reinforce the efficiency of these treatments of GBM patients.

Published
2010
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19. Identification of a lysine-rich region of Fas as a raft nanodomain targeting signal necessary for Fas-mediated cell death

Author

Nadia Lounnas, Aurélie Rossin, Anne-Odile Hueber, Sébastien Mailfert, Didier Marguet, Krittalak Chakrabandhu, Rosana Kral, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Cytoskeletal Proteins, T-Lymphocytes, MESH: Membrane Microdomains, Fluorescent Antibody Technique, Apoptosis, Fas ligand, TNF-Related Apoptosis-Inducing Ligand, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Animals, Internalization, Cytoskeleton, MESH: Fluorescent Antibody Technique, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cells, Cultured, media_common, 0303 health sciences, MESH: Immunoblotting, Reverse Transcriptase Polymerase Chain Reaction, Raft, Fas receptor, Cell biology, MESH: Antigens, CD95, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), MESH: TNF-Related Apoptosis-Inducing Ligand, Signal Transduction, MESH: Cells, Cultured, MESH: Cell Nucleus, Fas Ligand Protein, MESH: Mutation, Lipoylation, media_common.quotation_subject, Immunoblotting, MESH: Lipoylation, macromolecular substances, Biology, 03 medical and health sciences, Membrane Microdomains, Palmitoylation, MESH: Cytoskeleton, Animals, Humans, Immunoprecipitation, MESH: Lysine, RNA, Messenger, fas Receptor, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Cell Nucleus, MESH: Humans, MESH: Immunoprecipitation, Lysine, MESH: Apoptosis, fungi, Cell Biology, Actin cytoskeleton, MESH: Fas Ligand Protein, Cytoskeletal Proteins, MESH: T-Lymphocytes, Cytoplasm, Mutation
Abstract

International audience; Fas interaction at the plasma membrane with its lipid and protein environment plays a crucial role in the early steps of Fas signalling induced by Fas ligand binding. Particularly, Fas localisation in the raft nanodomains, ezrin-mediated interaction with the actin cytoskeleton and subsequent internalization are critical steps in Fas-mediated cell death. We identified a lysine-rich region (LRR) in the cytoplasmic, membrane-proximal region of Fas as a key determinant modulating these initial events. Through a genetic approach, we demonstrate that Fas LRR represents another signal additional to palmitoylation targeting Fas to the raft nanodomains, and modulates Fas interaction with the cytoskeleton.

Published
2010
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20. Cisplatin-induced apoptosis involves a Fas-ROCK-ezrin-dependent actin remodelling in human colon cancer cells

Author

Odile Sergent, Amélie Rébillard, Xavier Tekpli, Mathieu Pizon, Dominique Lagadic-Gossmann, Patrick Legembre, Elodie Jouan, Marie-Thérèse Dimanche-Boitrel, David Gilot, S. Jouan-Lanhouet, Environmental and food chemical toxicants membrane and gene targets, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2, ifr 66, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Ligue Nationale Contre le Cancer (Côte d'Armor, Ille et Vilaine et Loire-Atlantique Comités), Rennes Métropole et la Région Bretagne., École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR)-Université de Rennes (UR), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC)

Subjects
MESH: Signal Transduction, Cancer Research, RHOA, MESH: Cytoskeletal Proteins, Apoptosis, Ezrin, Fas ligand, 0302 clinical medicine, RNA interference, Tumor Cells, Cultured, FADD, Membrane fluidity, Cytoskeleton, 0303 health sciences, biology, Actin cytoskeleton, RhoA-GTP, Fas receptor, Colon cancer, MESH: Antigens, CD95, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Signal Transduction, Fas Ligand Protein, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, ROCK, Humans, fas Receptor, MESH: Tumor Cells, Cultured, Lipid rafts, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Apoptosis, Fas, MESH: Fas Ligand Protein, Cytoskeletal Proteins, MESH: Cisplatin, biology.protein, Cancer research, MESH: Antineoplastic Agents, Cisplatin
Abstract

International audience; In human colon cancer cells, cisplatin-induced apoptosis involves the Fas death receptor pathway independent of Fas ligand. The present study explores the role of ezrin and actin cytoskeleton in relation with Fas receptor in this cell death pathway. In response to cisplatin treatment, a rapid and transient actin reorganisation is observed at the cell membrane by fluorescence microscopy after Phalloidin-FITC staining. This event is dependent on the membrane fluidification studied by electron paramagnetic resonance and necessary for apoptosis induction. Moreover, early after the onset of cisplatin treatment, ezrin co-localised with Fas at the cell membrane was visualised by membrane microscopy and was redistributed with Fas, FADD and procaspase-8 into membrane lipid rafts as shown on Western blots. In fact, cisplatin exposure results in an early small GTPase RhoA activation demonstrated by RhoA-GTP pull down, Rho kinase (ROCK)-dependent ezrin phosphorylation and actin microfilaments remodelling. Pretreatment with latrunculin A, an inhibitor of actin polymerisation, or specific extinction of ezrin or ROCK by RNA interference prevents both cisplatin-induced actin reorganisation and apoptosis. Interestingly, specific extinction of Fas receptor by RNA interference abrogates cisplatin-induced ROCK-dependent ezrin phosphorylation, actin reorganisation and apoptosis suggesting that Fas is a key regulator of cisplatin-induced actin remodelling and is indispensable for apoptosis. Thus, these findings show for the first time that phosphorylation of ezrin by ROCK via Fas receptor is involved in the early steps of cisplatin-induced apoptosis.

Published
2010
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21. Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization

Author

Emma R. Isaac, Bruno J. Gonzalez, Delphine Burel, Ludovic Galas, Alain Fournier, Pierre Chapillon, Nancy M. Sherwood, Bénédicte Parent, Vincent Roy, Sébastien Arthaud, Hubert Vaudry, Arnaud Desfeux, Aurélie Allais, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Biology, University of Victoria [Canada] (UVIC), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), and Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Cell Death, Cerebellum, Time Factors, MESH: Neurons, Biochemistry, MESH: Mice, Knockout, Fas ligand, MESH: Animals, Newborn, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, MESH: Behavior, Animal, MESH: Caspase 3, MESH: Animals, Caspase, MESH: Cell Size, MESH: Bromodeoxyuridine, Mice, Knockout, Neurons, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Statistics, Nonparametric, biology, Behavior, Animal, Cell Death, Caspase 3, Gene Expression Regulation, Developmental, MESH: Motor Activity, Pituitary adenylate cyclase-activating peptide, medicine.anatomical_structure, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Pituitary Adenylate Cyclase-Activating Polypeptide, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, Programmed cell death, endocrine system, Fas Ligand Protein, MESH: Reflex, MESH: Psychomotor Performance, In Vitro Techniques, Motor Activity, Statistics, Nonparametric, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Cell Proliferation, Reflex, medicine, Animals, RNA, Messenger, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Cell Proliferation, Cell Size, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Time Factors, Granule cell, MESH: Cerebellum, MESH: Fas Ligand Protein, Mice, Inbred C57BL, Endocrinology, Animals, Newborn, Bromodeoxyuridine, Apoptosis, biology.protein, 030217 neurology & neurosurgery, Psychomotor Performance
Abstract

International audience; It is now established that the development of the CNS requires equilibrium between cell survival and apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a powerful protective effect on cerebellar granule cells by inhibiting the caspase 3. In contrast, Fas ligand (FasL) plays an essential role during ontogenesis in eliminating supernumerary neurons by apoptosis. To determine if PACAP and FasL interact during cerebellar development, we characterized the effects of these factors on cerebellar morphogenesis and caspase 3 activity in PACAP+/+ and PACAP-/- mice. First, we demonstrated in vivo that PACAP is able to reverse the diminution of internal granule cell layer thickness induced by FasL in PACAP+/+ and PACAP-/- mice. Second, ex vivo and immunohistochemical studies revealed that interaction between FasL and PACAP occurs through the caspase 3 activity. Third, behavioural study showed a significant difference for the PACAP + FasL group in the righting reflex test at P8 which does not persist at P60. Finally, a time course study revealed that the pro-apoptotic effect of FasL characterized at P8 was followed by a progressive compensatory mechanism in caspase 3 activity and bromodeoxyuridine incorporation. These data suggest that PACAP and FasL interact during cerebellar development to control apoptosis of granule cells and may affect some motor cerebellar functions.

Published
2010
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22. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Author

Olivia Bonduelle, Daniel Alvarez-Fischer, Richard A. Flavell, Yasmina Laouar, Vanessa Brochard, Virginie Beray-Berthat, Jean-Marie Launay, Stéphane Hunot, Annick Prigent, Charles Duyckaerts, Jacques Callebert, Aline Perrin, Etienne C. Hirsch, Béhazine Combadière, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Section of Immunobiology, Yale University School of Medicine, Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR6, The Michael J. Fox Foundation, Fondation pour la Recherche sur le Cerveau, Fondation France Parkinson, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Yale School of Medicine [New Haven, Connecticut] (YSM), and Hunot, Stéphane

Subjects
CD4-Positive T-Lymphocytes, Male, MESH: Cell Death, Lymphocyte, Dopamine, Parkinson's disease, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, MESH: Mice, Knockout, MESH: Nerve Degeneration, Mice, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Animals, Aged, 80 and over, Mice, Knockout, Neurons, MESH: Aged, 0303 health sciences, Cell Death, Neurodegeneration, Dopaminergic, Brain, MESH: CD4-Positive T-Lymphocytes, Parkinson Disease, General Medicine, adaptive immunity, Acquired immune system, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, Fas Ligand Protein, MESH: Interferon-gamma, chemical and pharmacologic phenomena, MESH: Dopamine, Biology, lymphocyte, 03 medical and health sciences, Interferon-gamma, MESH: Brain, Immune system, Parkinsonian Disorders, MESH: Mice, Inbred C57BL, Dopaminergic Cell, MESH: Homeodomain Proteins, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Immunodeficient Mouse, Aged, Homeodomain Proteins, Innate immune system, MESH: Humans, MESH: Immune System, MESH: Parkinsonian Disorders, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Male, MESH: Fas Ligand Protein, Mice, Inbred C57BL, Disease Models, Animal, Immune System, Immunology, Nerve Degeneration, MESH: Disease Models, Animal, 030217 neurology & neurosurgery, MESH: Parkinson Disease
Abstract

International audience; Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Published
2009
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23. Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway

Author

Sophie Daburon, Patrick Moreau, Amélie Rébillard, Benjamin Chaigne-Delalande, Marie Bénéteau, Jean-Luc Taupin, Patrick Legembre, Francesca De Giorgi, François Ichas, Jean-François Moreau, Marie-Thérèse Dimanche-Boitrel, Mathieu Pizon, Université Bordeaux Segalen - Bordeaux 2, ifr 66, Institut National de la Santé et de la Recherche Médicale (INSERM), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Immunologie Pellegrin (IMMUNOLOGIE), CHU de Bordeaux Pellegrin [Bordeaux], Association pour la Recherche sur le Cancer grant 3798, La Fondation de France (Leucémie), La Ligue Contre le Cancer (Comité de la Dordogne), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
MESH: Cell Death, MESH: Signal Transduction, Cancer Research, MESH: Membrane Microdomains, Apoptosis, PI3K, Fas ligand, MESH: Down-Regulation, Wortmannin, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Enzyme Inhibitors, Lipid raft, Phosphoinositide-3 Kinase Inhibitors, 0303 health sciences, Cell Death, Phospholipid Ethers, Fas receptor, Cell biology, MESH: Antigens, CD95, Protein Transport, Oncology, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, CD95, Phosphatidylinositol 3-kinase signaling, Signal transduction, Signal Transduction, Edelfosine, MESH: Phospholipid Ethers, MESH: Protein Transport, MESH: Enzyme Activation, Fas Ligand Protein, MESH: Cell Line, Tumor, Down-Regulation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Membrane Microdomains, Cell Line, Tumor, Humans, fas Receptor, Phosphatidylinositol, Molecular Biology, Lipid rafts, 030304 developmental biology, MESH: Humans, MESH: Proto-Oncogene Proteins c-akt, MESH: Fas Ligand Protein, Enzyme Activation, chemistry, MESH: Phosphatidylinositol 3-Kinases, Cancer research, Proto-Oncogene Proteins c-akt
Abstract

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction. Furthermore, similarly to edelfosine, blockade of the PI3K activity, using specific inhibitors LY294002 and wortmannin, leads to the clustering of Fas whose supramolecular complex is colocalized within the lipid rafts. These findings indicate that the antitumoral agent edelfosine down-modulates the PI3K signal to sensitize tumor cells to death through the redistribution of Fas into large platform of membrane rafts. (Mol Cancer Res 2008;6(4):604–13)

Published
2008
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24. Dendritic cells and innate defense against tumor cells

Author

Grégoire Mignot, Evelyn Ullrich, Magali Terme, Nathalie Chaput, Laurence Chaperot, Caroline Flament, Cédric Ménard, Mathieu Bonmort, Laurence Zitvogel, Joel Plumas, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 9 (Immunobiologie et Immunothérapie des Cancers), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire recherche et développement, EFS, Laboratoire recherche et développement, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARC, INCA, Cancéropole, ligue nationale contre le cancer, Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaperot, Laurence

Subjects
MESH: Interferon Type I, Endocrinology, Diabetes and Metabolism, MESH: Interleukin-15, MESH: Piperazines, Apoptosis, Piperazines, MESH: Cancer Vaccines, MESH: Uric Acid, 0302 clinical medicine, MESH: HMGB1 Protein, Neoplasms, Immunology and Allergy, MESH: Interferons, MESH: Neoplasms, HMGB1 Protein, MESH: CpG Islands, Interleukin-15, 0303 health sciences, Toll-like receptor, MESH: Cytokines, MESH: Dendritic Cells, T helper cell, T-Lymphocytes, Helper-Inducer, MESH: Granulocyte-Macrophage Colony-Stimulating Factor, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, Benzamides, Interferon Type I, Imatinib Mesylate, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Killer Cells, Natural, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Interferon Type II, T cell, Immunology, MESH: Receptor Cross-Talk, Biology, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Immune system, medicine, Biomarkers, Tumor, Humans, MESH: T-Lymphocytes, Helper-Inducer, Antigen-presenting cell, 030304 developmental biology, MESH: Immunity, Natural, Tumor microenvironment, Innate immune system, MESH: Humans, MESH: Apoptosis, Granulocyte-Macrophage Colony-Stimulating Factor, Dendritic cell, Dendritic Cells, Receptor Cross-Talk, Immunity, Innate, MESH: Fas Ligand Protein, Uric Acid, Pyrimidines, MESH: Pyrimidines, MESH: Tumor Markers, Biological, MESH: Oligodeoxyribonucleotides, CpG Islands, Interferons
Abstract

International audience; Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells.

Published
2008
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25. Requirement for Daxx in mature T-cell proliferation and activation

Author

Luci C, Leal-Sanchez J, Arnaud Couzinet, Krittalak Chakrabandhu, David C. Hancock, Anjuere F, Anne-Odile Hueber, Abdel-Sater F, Stebe E, Aurélie Rossin, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Immunité muqueuse et vaccination, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lincoln's Inn Fields Laboratories, and Cancer Research UK

Subjects
T-Lymphocytes, Apoptosis, Lymphocyte Activation, Fas ligand, chemistry.chemical_compound, Jurkat Cells, Mice, 0302 clinical medicine, MESH: Jurkat Cells, MESH: Animals, Genes, Dominant, 0303 health sciences, Mice, Inbred BALB C, ZAP70, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Fas receptor, Cell biology, MESH: Antigens, CD95, Mice, Inbred DBA, 030220 oncology & carcinogenesis, Caspases, Mitogen-Activated Protein Kinases, Co-Repressor Proteins, Programmed cell death, Fas Ligand Protein, MESH: Mice, Transgenic, MESH: Mice, Inbred BALB C, Mice, Transgenic, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Death-associated protein 6, MESH: Mice, Inbred C57BL, MESH: Intracellular Signaling Peptides and Proteins, MESH: Cell Proliferation, Animals, Humans, fas Receptor, MESH: Lymphocyte Activation, Molecular Biology, MESH: Mice, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Cell Proliferation, MESH: Adaptor Proteins, Signal Transducing, MESH: Caspases, MESH: Humans, MESH: Mice, Inbred DBA, Cell growth, MESH: Apoptosis, T-cell receptor, JNK Mitogen-Activated Protein Kinases, Tyrosine phosphorylation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: JNK Mitogen-Activated Protein Kinases, MESH: Mitogen-Activated Protein Kinases, MESH: Fas Ligand Protein, Mice, Inbred C57BL, MESH: T-Lymphocytes, chemistry, Carrier Proteins, MESH: Genes, Dominant, MESH: Nuclear Proteins, Molecular Chaperones
Abstract

The protein Daxx promotes Fas-mediated cell death through activation of apoptosis signal-regulating kinase 1, leading to the activation of the MAPKs JNK and p38. Owing to the in utero lethality of daxx-deficient mice, the in vivo role of Daxx has been so far difficult to analyze. We have generated transgenic mice expressing a dominant-negative form of Daxx (Daxx-DN) in the T-cell lineage. We show that Daxx is recruited to the Fas receptor upon FasL engagement and that Daxx-DN expression protects activated T cells from Fas-induced cell death, by preventing the death-inducing signal complex to be properly formed. Normal lymphocyte development and homeostasis are nevertheless observed. Interestingly, we report that both in vitro and in vivo stimulation of Daxx-DN T-lymphocytes leads to increased proliferative T-cell responses. This increased proliferation is associated with a marked increase in tyrosine phosphorylation of LAT and ZAP70 as Daxx-DN favor their recruitment to the T-cell receptor (TCR) complex. These findings identify Daxx as a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death.

Published
2007
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26. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts

Author

Yoshifumi Harada, Jun Kanno, Yuuki Imai, Katsuhide Igarashi, Shu Takeda, Takahiro Matsumoto, Yoko Yamamoto, Daniel Metzger, Pierre Chambon, Andrée Krust, Shingo Sato, Kunio Takaoka, T. John Martin, Hiroshi Takayanagi, Kazusane Takeuchi, Takashi Nakamura, Shigeaki Kato, Hiroshi Nishina, Yoshiaki Azuma, Institute of Laser Engineering (ILE), Osaka University [Osaka], Pfizer Japan Incorporated (NAGOYA LABORATORIES), Pfizer, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Male, MESH: Integrases, Cathepsin K, HUMDISEASE, Estrogen receptor, Osteoclasts, DEVBIO, Apoptosis, MESH: Mice, Knockout, Fas ligand, Mice, 0302 clinical medicine, Bone Density, MESH: Osteoclasts, MESH: Animals, MESH: Estrogen Receptor alpha, MESH: Bone Density, Cells, Cultured, Mice, Knockout, 0303 health sciences, Estradiol, Cell Differentiation, MESH: Selective Estrogen Receptor Modulators, MESH: Antigens, CD95, Phenotype, SIGNALING, Mice, Inbred DBA, Female, MESH: Estradiol, Bone Remodeling, hormones, hormone substitutes, and hormone antagonists, medicine.drug, MESH: Cells, Cultured, Signal Transduction, MESH: Cell Differentiation, Selective Estrogen Receptor Modulators, medicine.medical_specialty, Fas Ligand Protein, medicine.drug_class, MESH: Mice, Transgenic, Ovariectomy, MESH: Ovariectomy, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, MESH: Phenotype, General Biochemistry, Genetics and Molecular Biology, Bone resorption, 03 medical and health sciences, Downregulation and upregulation, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Bone Remodeling, medicine, Animals, fas Receptor, MESH: Mice, Estrogen receptor beta, 030304 developmental biology, MESH: Mice, Inbred DBA, Integrases, Biochemistry, Genetics and Molecular Biology(all), MESH: Apoptosis, Estrogen Receptor alpha, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cathepsins, MESH: Fas Ligand Protein, MESH: Male, Mice, Inbred C57BL, Bone Diseases, Metabolic, Tamoxifen, Endocrinology, Estrogen, MESH: Cathepsins, MESH: Tamoxifen, Estrogen receptor alpha, MESH: Female, MESH: Bone Diseases, Metabolic
Abstract

Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.

Published
2007
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27. Fas ligand is localized to membrane rafts where it displays increased cell death-inducing activity

Author

Vladimir Kirkin, Martin Zörnig, L. Wawrezinieck, Fabien Conchonaud, Nathalie Cahuzac, Ottmar Janssen, Didier Marguet, Wiebke Baum, Anne-Odile Hueber, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institute of Immunology, University Hospital Schleswig-Holstein, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Guglietta, Noëlle

Subjects
Cell, MESH: Membrane Glycoproteins, MESH: Membrane Microdomains, Apoptosis, Biochemistry, Fas ligand, 0302 clinical medicine, Receptor, Lipid raft, Sequence Deletion, 0303 health sciences, Membrane Glycoproteins, hemic and immune systems, Hematology, MESH: Tumor Necrosis Factors, MESH: Sequence Deletion, Fas receptor, Cell biology, MESH: Antigens, CD95, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Tumor Necrosis Factors, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Intracellular, Protein Binding, Cell signaling, Programmed cell death, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, 03 medical and health sciences, Membrane Microdomains, medicine, Humans, MESH: Protein Binding, fas Receptor, 030304 developmental biology, MESH: Humans, Cholesterol Oxidase, MESH: Apoptosis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Fas Ligand Protein, MESH: Cell Line, MESH: Cholesterol Oxidase
Abstract

Fas ligand (FasL), a member of the TNF protein family, potently induces cell death by activating its matching receptor Fas. Fas-mediated killing plays a critical role in naturally and pathologically occurring cell death, including development and homeostasis of the immune system. In addition to its receptor-interacting and cell death–inducing extracellular domain, FasL has a well-conserved intracellular portion with a proline-rich SH3 domain–binding site probably involved in non-apoptotic functions. We report here that, as with the Fas receptor, a fraction of FasL is constitutively localized in rafts. These dynamic membrane microdomains, enriched in sphingolipids and cholesterol, are important for cell signaling and trafficking processes. We show that FasL is partially localized in rafts and that increased amounts of FasL are found in rafts after efficient FasL/Fas receptor interactions. Raft disorganization after cholesterol oxidase treatment and deletions within the intracellular FasL domain diminish raft partitioning and, most important, lead to decreased FasL killing. We conclude that FasL is recruited into lipid rafts for maximum Fas receptor contact and cell death–inducing potency. These findings raise the possibility that certain pathologic conditions may be treated by altering the cell death–inducing capability of FasL with drugs affecting its raft localization.

Published
2006
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28. E2F1 induces apoptosis and sensitizes human lung adenocarcinoma cells to death-receptor-mediated apoptosis through specific downregulation of c-FLIP(short)

Author

Elisabeth Brambilla, Laurence Chaperot, Christian Brambilla, Olivier Micheau, Joel Plumas, Sylvie Gazzeri, Caroline Salon, Beatrice Eymin, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Michallon, INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Etablissement Français du Sang Rhône-Alpes, EFS, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Salas, Danielle

Subjects
MESH: CASP8 and FADD-Like Apoptosis Regulating Protein, MESH : RNA, Messenger, Lung Neoplasms, MESH : DNA, MESH : Cytotoxicity, Immunologic, MESH: Membrane Glycoproteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Apoptosis, MESH : Blotting, Western, MESH : Fluorescent Antibody Technique, Indirect, MESH: Down-Regulation, MESH : E2F1 Transcription Factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, TNF-Related Apoptosis-Inducing Ligand, MESH : Adenocarcinoma, 0302 clinical medicine, Cytotoxic T cell, Fluorescent Antibody Technique, Indirect, 0303 health sciences, Membrane Glycoproteins, MESH : Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, MESH: Tumor Necrosis Factors, Cell biology, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Caspases, Adenocarcinoma, Tumor necrosis factor alpha, MESH: TNF-Related Apoptosis-Inducing Ligand, endocrine system, MESH: Enzyme Activation, MESH : Gene Expression Regulation, Neoplastic, Blotting, Western, Down-Regulation, MESH : T-Lymphocytes, Cytotoxic, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Blotting, Western, Humans, MESH : Lung Neoplasms, RNA, Messenger, Molecular Biology, MESH: Humans, MESH: Caspases, Tumor Necrosis Factor-alpha, MESH : Humans, DNA, medicine.disease, MESH: Lung Neoplasms, Enzyme Activation, MESH: Tumor Necrosis Factor-alpha, Apoptosis Regulatory Proteins, MESH : Apoptosis, T-Lymphocytes, Cytotoxic, Cytotoxicity, Immunologic, MESH : Membrane Glycoproteins, MESH : Fas Ligand Protein, MESH: Caspase 8, Fas ligand, MESH : Down-Regulation, MESH : TNF-Related Apoptosis-Inducing Ligand, MESH: Reverse Transcriptase Polymerase Chain Reaction, E2F1, MESH : Tumor Necrosis Factor-alpha, Caspase 8, MESH : Caspase 8, Reverse Transcriptase Polymerase Chain Reaction, MESH: DNA, MESH: Gene Expression Regulation, Neoplastic, MESH: E2F1 Transcription Factor, Tumor Necrosis Factors, biological phenomena, cell phenomena, and immunity, MESH : Apoptosis Regulatory Proteins, Programmed cell death, MESH: Cell Line, Tumor, Fas Ligand Protein, MESH : Tumor Necrosis Factors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Downregulation and upregulation, MESH : Intracellular Signaling Peptides and Proteins, MESH: Intracellular Signaling Peptides and Proteins, Cell Line, Tumor, medicine, MESH: Fluorescent Antibody Technique, Indirect, MESH: Cytotoxicity, Immunologic, 030304 developmental biology, MESH: RNA, Messenger, MESH : Cell Line, Tumor, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH: Adenocarcinoma, Cell Biology, MESH : CASP8 and FADD-Like Apoptosis Regulating Protein, MESH: Fas Ligand Protein, Cancer research, MESH : Caspases, MESH : Enzyme Activation, MESH: T-Lymphocytes, Cytotoxic, E2F1 Transcription Factor
Abstract

E2F1 is a transcription factor that plays a well-documented role during S phase progression and apoptosis. We had previously postulated that the low level of E2F1 in primary lung adenocarcinoma contributes to their carcinogenesis. Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex. Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells. Finally, we describe the specific overexpression of c-FLIP(S) in human lung adenocarcinomas with low level of E2F1. Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.

Published
2005
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29. An anti-CD19 antibody coupled to a tetanus toxin peptide induces efficient Fas ligand (FasL)-mediated cytotoxicity of a transformed human B cell line by specific CD4+ T cells

Author

Yu Z, Gérard Eberl, S Jiang, Giampietro Corradin, Pascal Schneider, Jean-Pierre Mach, Institute of Biochemistry, University of Lausanne and ISREC, Epalinges, Switzerland., and Hugot, Bérengère

Subjects
CD4-Positive T-Lymphocytes, Fas Ligand Protein, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Antigens, CD19, Immunology, B-cell receptor, Naive B cell, MESH: Membrane Glycoproteins, MESH: Cytotoxicity Tests, Immunologic, CD19, Epitope, MESH: Antibodies, Monoclonal, 03 medical and health sciences, 0302 clinical medicine, Tetanus Toxin, MESH: B-Lymphocytes, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, MESH: Cell Line, Transformed, MESH: Tetanus Toxin, Antigen-presenting cell, B cell, Cell Line, Transformed, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, Membrane Glycoproteins, MESH: Humans, biology, MESH: Antigens, CD19, MESH: Peptides, Antibodies, Monoclonal, MESH: CD4-Positive T-Lymphocytes, Cytotoxicity Tests, Immunologic, Molecular biology, MESH: Fas Ligand Protein, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, Peptides
Abstract

SUMMARYTreatment of B cell lymphoma patients with MoAbs specific for the common B cell marker (CD20) has shown a good overall response rate, but the number of complete remissions is still very low. The use of MoAbs coupled to radioisotopes can improve the results, but induces undesirable myelodepression. As an alternative, we proposed to combine the specificity of MoAbs with the immunogenicity of T cell epitopes. We have previously shown that an anti-Igλ MoAb coupled to an MHC class II-restricted universal T cell epitope peptide P2 derived from tetanus toxin induces efficient lysis of a human B cell lymphoma by a specific CD4+ T cell line. Here we demonstrate that the antigen presentation properties of the MoAb–peptide conjugate are maintained using a MoAb directed against a common B cell marker, CD19, which is known to be co-internalized with the B cell immunoglobulin receptor. In addition, we provide evidence that B cell lysis is mediated by the Fas apoptosis pathway, since Fas (CD95), but not tumour necrosis factor receptor (TNFr) or TNF-related receptors, is expressed by the target B cells, and FasL, but not perforin, is expressed by the effector T cells. These results show that B cell lymphomas can be ‘foreignized’ by MoAb–peptide P2 conjugates directed against the common B cell marker CD19 and eliminated by peptide P2-specific CD4+ T cells, via the ubiquitous Fas receptor. This approach, which bridges the specificity of passive antibody therapy with an active T cell immune response, may be complementary to and more efficient than the present therapy results with unconjugated chimeric anti-CD20 MoAbs.

Published
1998

30. Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Author

Christopher E. Henderson, Patrick Aebischer, Brigitte Pettmann, Cédric Raoul, Emmanuelle Buhler, Georg Haase, Christel Sadeghi, Arnaud Jacquier, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Haase, Georg, Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Mice, Mutant Strains, MESH: Membrane Glycoproteins, Polymerase Chain Reaction, Fas ligand, MESH: Spinal Cord, Mice, Superoxide Dismutase-1, 0302 clinical medicine, MESH: Motor Neuron Disease, MESH: Animals, Nuclear protein, Amyotrophic lateral sclerosis, Receptor, MESH: Superoxide Dismutase, Motor Neurons, 0303 health sciences, Membrane Glycoproteins, Multidisciplinary, MESH: Feedback, MESH: Polymorphism, Single Nucleotide, musculoskeletal, neural, and ocular physiology, Homozygote, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, MESH: Tumor Necrosis Factors, Biological Sciences, musculoskeletal system, MESH: Crosses, Genetic, Cell biology, MESH: Antigens, CD95, Spinal Cord, MESH: Models, Animal, embryonic structures, Models, Animal, Tumor Necrosis Factors, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Co-Repressor Proteins, tissues, MESH: Motor Neurons, MESH: Homozygote, Programmed cell death, Fas Ligand Protein, MESH: Mice, Transgenic, Transgene, SOD1, Mice, Transgenic, MESH: Carrier Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Nitric Oxide, Polymorphism, Single Nucleotide, Feedback, 03 medical and health sciences, Death-associated protein 6, MESH: Mice, Inbred C57BL, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, fas Receptor, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Motor Neuron Disease, MESH: Mice, Crosses, Genetic, 030304 developmental biology, Superoxide Dismutase, nutritional and metabolic diseases, MESH: Polymerase Chain Reaction, medicine.disease, Molecular biology, Mice, Mutant Strains, MESH: Fas Ligand Protein, MESH: Male, Mice, Inbred C57BL, nervous system, MESH: Nitric Oxide, Carrier Proteins, MESH: Nuclear Proteins, MESH: Female, 030217 neurology & neurosurgery, Molecular Chaperones
Abstract

The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1 G93A and SOD1 G85R , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro . In vivo , mutant SOD1 G93A and SOD1 G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.

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