HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases
| Autor: | Lee, Jung-Hyun, Wittki, Sebastian, Bräu, Tanja, Dreyer, Florian S., Krätzel, Kirsten, Dindorf, Jochen, Johnston, Ian C.D., Gross, Stefanie, Kremmer, Elisabeth, Zeidler, Reinhard, Schlötzer-Schrehardt, Ursula, Lichtenheld, Mathias, Saksela, Kalle, Harrer, Thomas, Schuler, Gerold, Federico, Maurizio, Baur, Andreas S. |
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| Rok vydání: | 2012 |
| Předmět: |
ADAM10
HIV Infections Heterogeneous-Nuclear Ribonucleoprotein K ADAM10 Protein 0302 clinical medicine Tumor Cells Cultured Phosphorylation Lipid raft Melanoma 0303 health sciences Effector Polycomb Repressive Complex 2 3. Good health Protein Kinase C-delta Protein Transport Ribonucleoproteins 030220 oncology & carcinogenesis Protein Binding Signal Transduction Proteases Integrin macromolecular substances Biology ADAM17 Protein 03 medical and health sciences Membrane Microdomains Humans Secretion nef Gene Products Human Immunodeficiency Virus Protein Precursors Molecular Biology Paxillin 030304 developmental biology Adaptor Proteins Signal Transducing Tumor Necrosis Factor-alpha Secretory Vesicles Membrane Proteins Cell Biology Enzyme Activation ADAM Proteins HEK293 Cells Amino Acid Substitution p21-Activated Kinases Case-Control Studies Cancer cell biology.protein Cancer research Mutagenesis Site-Directed Amyloid Precursor Protein Secretases Protein Processing Post-Translational |
| Zdroj: | Mol. Cell 49, 668-679 (2013) |
| ISSN: | 1097-4164 |
| Popis: | The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin effector paxillin to recruit and activate TNF alpha converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNF alpha and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNF alpha. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment. |
| Databáze: | OpenAIRE |
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