9 results on '"Laffert B"'
Search Results
2. Induction of HIV transcription by Nef involves Lck activation and protein kinase Cθ raft recruitment leading to activation of ERK1/2 but not NFκB
- Author
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Witte, V., primary, Laffert, B., additional, Gintschel, P., additional, Krautkrämer, E., additional, Blume, K., additional, Fackler, O. T., additional, and Baur, A. S., additional
- Published
- 2009
- Full Text
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3. Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls.
- Author
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Wagner N, Eberhardt M, Vera J, Cuomo F, Blume K, Galster S, Achenbach S, Laffert B, Kahlert H, Schuler G, Berking C, and Baur A
- Abstract
Background: Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed., Objectives: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors., Methods: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches., Results: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array., Conclusions: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed., Competing Interests: BL and HK are employees of Allergopharma GmbH & Co. KG., (© 2021 The Author(s).)
- Published
- 2021
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4. Induction of HIV transcription by Nef involves Lck activation and protein kinase C theta raft recruitment leading to activation of ERK1/2 but not NF kappa B.
- Author
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Witte V, Laffert B, Gintschel P, Krautkrämer E, Blume K, Fackler OT, and Baur AS
- Subjects
- Cell Line, Enzyme Activation genetics, Gene Expression Regulation, Viral, Humans, Isoenzymes deficiency, Isoenzymes genetics, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) deficiency, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) genetics, MAP Kinase Signaling System genetics, Membrane Microdomains virology, NF-kappa B metabolism, Protein Kinase C deficiency, Protein Kinase C genetics, Protein Kinase C-theta, Protein Transport genetics, T-Lymphocytes enzymology, T-Lymphocytes metabolism, T-Lymphocytes virology, Up-Regulation genetics, HIV-1 genetics, Isoenzymes physiology, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Membrane Microdomains enzymology, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Protein Kinase C physiology, nef Gene Products, Human Immunodeficiency Virus physiology
- Abstract
The Nef protein of HIV-1 is a key promoter of disease progression, owing to its dramatic yet ill-defined impact on viral replication. Previously, we have shown that Nef enhances Tat-mediated transcription in a manner depending on Lck and the cytoplasmic sequestration of the transcriptional repressor embryonic ectodermal development [corrected]. In this study, we report that Lck is activated by Nef and targets protein kinase Ctheta downstream, leading to the translocation of the kinase into membrane microdomains. Although microdomain-localized protein kinase Ctheta is thought to induce the transcription factor NFkappaB, we unexpectedly failed to correlate Nef-induced signaling events with enhanced NFkappaB activity. Instead, we observed an increase in ERK MAPK activity. We conclude that Nef-mediated signaling cooperates with Nef-induced derepression and supports HIV transcription through an ERK MAPK-dependent, but NFkappaB-independent, pathway.
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- 2008
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5. HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane.
- Author
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Witte V, Laffert B, Rosorius O, Lischka P, Blume K, Galler G, Stilper A, Willbold D, D'Aloja P, Sixt M, Kolanus J, Ott M, Kolanus W, Schuler G, and Baur AS
- Subjects
- Amino Acid Sequence, Blotting, Western, Chromatin metabolism, Cytoplasm metabolism, Glutathione Transferase metabolism, Humans, Integrins chemistry, Jurkat Cells, Microscopy, Fluorescence, Models, Biological, Molecular Sequence Data, Plasmids metabolism, Polycomb Repressive Complex 2, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein Transport, Recombinant Fusion Proteins metabolism, Sequence Homology, Amino Acid, Signal Transduction, Time Factors, Transcription, Genetic, Two-Hybrid System Techniques, nef Gene Products, Human Immunodeficiency Virus, Cell Membrane metabolism, Gene Products, nef metabolism, Gene Products, nef physiology, HIV metabolism, Repressor Proteins metabolism
- Abstract
The Nef protein of human and simian immunodeficiency virus (HIV/SIV) is believed to interfere with T cell activation signals by forming a signaling complex at the plasma membrane. Composition and function of the complex are not fully understood. Here we report that Nef recruits the Polycomb Group (PcG) protein Eed, so far known as a nuclear factor and repressor of transcription, to the membrane of cells. The Nef-induced translocation of Eed led to a potent stimulation of Tat-dependent HIV transcription, implying that Eed removal from the nucleus is required for optimal Tat function. Similar to Nef action, activation of integrin receptors recruited Eed to the plasma membrane, also leading to enhanced Tat/Nef-mediated transcription. Our results suggest a link between membrane-associated activation processes and transcriptional derepression and demonstrate how HIV exploits this mechanism.
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- 2004
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6. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals.
- Author
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Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schürmann A, and Baur AS
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- 3T3 Cells, Animals, Apoptosis, Cell Line, Genes, nef, HIV-1 genetics, HIV-1 pathogenicity, Humans, Mice, Mutation, Phosphorylation, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins physiology, Proto-Oncogene Proteins c-akt, Signal Transduction, Transfection, Virus Replication, bcl-Associated Death Protein, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases, Carrier Proteins physiology, Gene Products, nef physiology, HIV-1 physiology, Phosphatidylinositol 3-Kinases physiology, Protein Serine-Threonine Kinases physiology
- Abstract
A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.
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- 2001
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7. A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells.
- Author
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Fackler OT, Wolf D, Weber HO, Laffert B, D'Aloja P, Schuler-Thurner B, Geffin R, Saksela K, Geyer M, Peterlin BM, Schuler G, and Baur AS
- Subjects
- Amino Acid Motifs, CD4 Antigens metabolism, CD8 Antigens genetics, CD8 Antigens metabolism, Cell Line, Dendritic Cells physiology, Gene Products, nef chemistry, Gene Products, nef metabolism, HIV-1 pathogenicity, Humans, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Models, Molecular, Precipitin Tests, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Structure, Tertiary, Receptors, Antigen, T-Cell metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, T-Lymphocytes virology, nef Gene Products, Human Immunodeficiency Virus, Gene Products, nef genetics, HIV-1 physiology, T-Lymphocytes physiology
- Abstract
In the infected host, the Nef protein of HIV/SIV is required for high viral loads and thus disease progression. Recent evidence indicates that Nef enhances replication in the T cell compartment after the virus is transmitted from dendritic cells (DC). The underlying mechanism, however, is not clear. Here, we report that a natural variability in the proline-rich motif (R71T) profoundly modulated Nef-stimulated viral replication in primary T cells of immature dendritic cell/T cell cocultures. Whereas both Nef variants (R/T-Nef) downregulated CD4, only the isoform supporting viral replication (R-Nef) efficiently interacted with signaling molecules of the T cell receptor (TCR) environment and stimulated cellular activation. Structural analysis suggested that the R to T conversion induces conformational changes, altering the flexibility of the loop containing the PxxP motif and hence its ability to bind cellular partners. Our report suggests that functionally and conformationally distinct Nef isoforms modulate HIV replication on the interaction level with the TCR-signaling environment once the virus enters the T cell compartment.
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- 2001
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8. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain.
- Author
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Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, and Baur AS
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- Fas Ligand Protein, HIV-1 physiology, Humans, Jurkat Cells, Protein Kinases metabolism, Protein Serine-Threonine Kinases metabolism, Up-Regulation, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases, Gene Products, nef metabolism, HIV-1 metabolism, Membrane Glycoproteins biosynthesis, Membrane Proteins metabolism, Receptors, Antigen, T-Cell metabolism
- Abstract
During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas-Fas ligand (FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression and apoptotic cell death of both CD4(+) and CD8(+) T cells by SIV is dependent on a functional nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL remained poorly understood. Here we report a direct association of HIV-1 Nef with the zeta chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR zeta chain. Conformation for the importance of zeta for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of zeta but not CD3epsilon was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein Nef contributes to the pathogenesis of HIV.
- Published
- 1999
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9. The N-terminus of Nef from HIV-1/SIV associates with a protein complex containing Lck and a serine kinase.
- Author
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Baur AS, Sass G, Laffert B, Willbold D, Cheng-Mayer C, and Peterlin BM
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- Amino Acid Sequence, HIV-1 immunology, Humans, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Macromolecular Substances, Molecular Sequence Data, Multiprotein Complexes, Oncogene Proteins, Viral analysis, Oncogene Proteins, Viral metabolism, Protein Binding immunology, Simian Immunodeficiency Virus immunology, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases, Gene Products, nef metabolism, HIV-1 metabolism, Protein Serine-Threonine Kinases metabolism, Simian Immunodeficiency Virus metabolism, src-Family Kinases metabolism
- Abstract
The Nef protein of human and primate lentiviruses is a key factor in HIV/SIV pathogenesis. Here we report that Nef associates with two different kinases, forming a multiprotein complex at the far N-terminus of the viral protein. One of the kinases was identified as Lck, whereas the second protein was found to be a serine kinase that phosphorylated Nef and Lck in vitro and could be discriminated from the serine kinase identified previously. The Nef-associated kinase complex (NAKC) was demonstrated in COS cells, in HIV-infected cells, and in vitro using recombinant Lck and Nef proteins. Deletion of a short amphipathic alpha-helix in the N-terminus, which was found to be conserved in all Nef proteins, inhibited association of the NAKC and significantly reduced virion infectivity.
- Published
- 1997
- Full Text
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