HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases.
Mol Cell
; 49(4): 668-79, 2013 Feb 21.
Article
em En
| MEDLINE
| ID: mdl-23317503
ABSTRACT
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 TNFα converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNFα and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNFα. 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas ADAM
/
Paxilina
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Secretases da Proteína Precursora do Amiloide
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Quinases Ativadas por p21
/
Produtos do Gene nef do Vírus da Imunodeficiência Humana
/
Proteínas de Membrana
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article