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Open Access Green as soon as Postprint is submitted to ZB.
HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases.
Mol. Cell 49, 668-679 (2013)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Necrosis-factor-alpha ; Group Protein Eed ; Type-1 Nef ; Infected Individuals ; Converting Enzyme ; Serine Kinase ; Growth-factor ; Tnf-alpha ; T-cells ; Phosphorylation
ISSN (print) / ISBN
1097-2765
e-ISSN
1097-4164
Journal
Molecular Cell
Quellenangaben
Volume: 49,
Issue: 4,
Pages: 668-679
Publisher
Elsevier
Reviewing status
Peer reviewed
Institute(s)
Institute of Molecular Immunology (IMI)