10 results on '"Heissmeyer V"'
Search Results
2. Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.
- Author
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Guo L, Salian S, Xue JY, Rath N, Rousseau J, Kim H, Ehresmann S, Moosa S, Nakagawa N, Kuroda H, Clayton-Smith J, Wang J, Wang Z, Banka S, Jackson A, Zhang YM, Wei ZJ, Hüning I, Brunet T, Ohashi H, Thomas MF, Bupp C, Miyake N, Matsumoto N, Mendoza-Londono R, Costain G, Hahn G, Di Donato N, Yigit G, Yamada T, Nishimura G, Ansel KM, Wollnik B, Hrabě de Angelis M, Mégarbané A, Rosenfeld JA, Heissmeyer V, Ikegawa S, and Campeau PM
- Subjects
- Humans, Mutation, Missense genetics, RNA, Ribosomal, 5.8S, RNA, RNA, Messenger genetics, Exoribonucleases genetics, Histones genetics
- Abstract
ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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3. Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells.
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Essig K, Hu D, Guimaraes JC, Alterauge D, Edelmann S, Raj T, Kranich J, Behrens G, Heiseke A, Floess S, Klein J, Maiser A, Marschall S, Hrabĕ de Angelis M, Leonhardt H, Calkhoven CF, Noessner E, Brocker T, Huehn J, Krug AB, Zavolan M, Baumjohann D, and Heissmeyer V
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes pathology, Cell Differentiation, Colitis genetics, Colitis pathology, Disease Models, Animal, Female, Forkhead Box Protein O1 genetics, Forkhead Box Protein O1 immunology, Gene Expression Regulation, Germinal Center immunology, Germinal Center pathology, Interleukin-2 Receptor alpha Subunit genetics, Interleukin-2 Receptor alpha Subunit immunology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs genetics, MicroRNAs immunology, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase immunology, Phosphatidylinositol 3-Kinases genetics, Primary Cell Culture, Repressor Proteins deficiency, Repressor Proteins genetics, Signal Transduction, Spleen immunology, Spleen pathology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory pathology, TOR Serine-Threonine Kinases genetics, Th17 Cells immunology, Th17 Cells pathology, Ubiquitin-Protein Ligases deficiency, Ubiquitin-Protein Ligases genetics, Colitis immunology, Phosphatidylinositol 3-Kinases immunology, Repressor Proteins immunology, TOR Serine-Threonine Kinases immunology, Ubiquitin-Protein Ligases immunology
- Abstract
Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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4. In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity.
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Halle S, Keyser KA, Stahl FR, Busche A, Marquardt A, Zheng X, Galla M, Heissmeyer V, Heller K, Boelter J, Wagner K, Bischoff Y, Martens R, Braun A, Werth K, Uvarovskii A, Kempf H, Meyer-Hermann M, Arens R, Kremer M, Sutter G, Messerle M, and Förster R
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- Animals, Calcium Signaling, Cell Communication, Cells, Cultured, Cytotoxicity, Immunologic, Humans, Immune Evasion, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Multiphoton, Perforin genetics, T-Lymphocyte Subsets virology, T-Lymphocytes, Cytotoxic virology, Herpesviridae Infections immunology, Muromegalovirus immunology, Perforin metabolism, T-Lymphocyte Subsets immunology, T-Lymphocytes, Cytotoxic immunology, Vaccinia immunology, Vaccinia virus immunology
- Abstract
According to in vitro assays, T cells are thought to kill rapidly and efficiently, but the efficacy and dynamics of cytotoxic T lymphocyte (CTL)-mediated killing of virus-infected cells in vivo remains elusive. We used two-photon microscopy to quantify CTL-mediated killing in mice infected with herpesviruses or poxviruses. On average, one CTL killed 2-16 virus-infected cells per day as determined by real-time imaging and by mathematical modeling. In contrast, upon virus-induced MHC class I downmodulation, CTLs failed to destroy their targets. During killing, CTLs remained migratory and formed motile kinapses rather than static synapses with targets. Viruses encoding the calcium sensor GCaMP6s revealed strong heterogeneity in individual CTL functional capacity. Furthermore, the probability of death of infected cells increased for those contacted by more than two CTLs, indicative of CTL cooperation. Thus, direct visualization of CTLs during killing of virus-infected cells reveals crucial parameters of CD8(+) T cell immunity., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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5. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells.
- Author
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Martinez GJ, Pereira RM, Äijö T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lähdesmäki H, Hogan PG, and Rao A
- Subjects
- Animals, Cells, Cultured, Clonal Anergy drug effects, Gene Expression Regulation genetics, Listeria monocytogenes immunology, Listeriosis immunology, Listeriosis microbiology, Lymphocyte Activation immunology, Mice, Mice, Transgenic, NFATC Transcription Factors genetics, Neoplasms immunology, Promoter Regions, Genetic genetics, Receptors, Antigen, T-Cell immunology, Recombinant Proteins genetics, CD8-Positive T-Lymphocytes immunology, Clonal Anergy genetics, NFATC Transcription Factors physiology, Recombinant Proteins pharmacology, Transcription Factor AP-1 metabolism
- Abstract
During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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6. Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.
- Author
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Gewies A, Gorka O, Bergmann H, Pechloff K, Petermann F, Jeltsch KM, Rudelius M, Kriegsmann M, Weichert W, Horsch M, Beckers J, Wurst W, Heikenwalder M, Korn T, Heissmeyer V, and Ruland J
- Subjects
- Animals, B-Lymphocytes immunology, Caspases deficiency, Cell Differentiation immunology, Gene Expression Regulation, Homeostasis immunology, Humans, Immunity, Mucosal immunology, Interferon-gamma biosynthesis, Lymphocyte Activation immunology, Mice, Mutant Strains, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Neoplasm Proteins deficiency, Nerve Degeneration immunology, Nerve Degeneration pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Antigen, T-Cell metabolism, Signal Transduction immunology, T-Lymphocytes, Regulatory immunology, Autoimmunity, Caspases metabolism, Inflammation immunology, Inflammation pathology, Neoplasm Proteins metabolism
- Abstract
The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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7. Tfh cell differentiation: missing Stat3 uncovers interferons' interference.
- Author
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Edelmann SL and Heissmeyer V
- Subjects
- Animals, Cell Differentiation, Interferon Type I metabolism, STAT3 Transcription Factor metabolism, T-Lymphocytes, Helper-Inducer cytology, T-Lymphocytes, Helper-Inducer metabolism
- Abstract
Viral infection induces a number of cytokines that shape T cell responses. In this issue of Immunity, Ray et al. (2014) describe how CD4(+) T cells decide on T follicular helper (Tfh) or T helper 1 (Th1) cell skewed gene expression during acute viral infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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8. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation.
- Author
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Vogel KU, Edelmann SL, Jeltsch KM, Bertossi A, Heger K, Heinz GA, Zöller J, Warth SC, Hoefig KP, Lohs C, Neff F, Kremmer E, Schick J, Repsilber D, Geerlof A, Blum H, Wurst W, Heikenwälder M, Schmidt-Supprian M, and Heissmeyer V
- Subjects
- Animals, CD4 Antigens metabolism, Cell Differentiation genetics, HEK293 Cells, Humans, Inducible T-Cell Co-Stimulator Protein genetics, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Protein Binding, Receptors, OX40 genetics, Repressor Proteins genetics, Ubiquitin-Protein Ligases genetics, Inducible T-Cell Co-Stimulator Protein metabolism, RNA, Messenger metabolism, Receptors, OX40 metabolism, Repressor Proteins metabolism, T-Lymphocytes, Helper-Inducer immunology, Ubiquitin-Protein Ligases metabolism
- Abstract
The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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9. FOXP3 controls regulatory T cell function through cooperation with NFAT.
- Author
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Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, and Rao A
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Binding Sites, Biomarkers metabolism, Cells, Cultured, Crystallography, X-Ray, Dimerization, Forkhead Transcription Factors chemistry, Forkhead Transcription Factors genetics, Genes, Reporter, Humans, Interleukin-2 genetics, Interleukin-2 metabolism, Jurkat Cells, Luciferases metabolism, Mice, Mice, Inbred NOD, Models, Molecular, Molecular Sequence Data, NFATC Transcription Factors chemistry, NFATC Transcription Factors genetics, Protein Binding, Protein Structure, Tertiary, Receptors, Interleukin-2 genetics, Receptors, Interleukin-2 metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Retroviridae genetics, Sequence Homology, Amino Acid, Up-Regulation, Forkhead Transcription Factors metabolism, NFATC Transcription Factors metabolism, T-Lymphocytes, Regulatory immunology
- Abstract
Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
- Published
- 2006
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10. Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation.
- Author
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Wegener E, Oeckinghaus A, Papadopoulou N, Lavitas L, Schmidt-Supprian M, Ferch U, Mak TW, Ruland J, Heissmeyer V, and Krappmann D
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, B-Cell CLL-Lymphoma 10 Protein, CARD Signaling Adaptor Proteins, CD4-Positive T-Lymphocytes metabolism, Cells, Cultured, Humans, Interleukin-2 metabolism, Jurkat Cells, Mice, Mice, Knockout, Models, Biological, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Multiprotein Complexes metabolism, Phosphorylation, Tumor Necrosis Factor-alpha metabolism, Adaptor Proteins, Signal Transducing metabolism, Apoptosis Regulatory Proteins metabolism, CD4-Positive T-Lymphocytes immunology, Caspases metabolism, Guanylate Kinases metabolism, I-kappa B Kinase physiology, Lymphocyte Activation, Neoplasm Proteins metabolism
- Abstract
T cell receptor (TCR) signaling to IkappaB kinase (IKK)/NF-kappaB is controlled by PKCtheta-dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex. Antigen-induced phosphorylation of Bcl10 has been reported, but its physiological function is unknown. Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. Thus, our data provide evidence that IKKbeta serves a dual role upstream of its classical substrates, the IkappaB proteins. While being essential for triggering initial CBM complex formation, IKKbeta-dependent phosphorylation of Bcl10 exhibits a negative regulatory role in T cell activation.
- Published
- 2006
- Full Text
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