HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases

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• 作者：Jung-Hyun Lee¹ ; Sebastian Wittki¹ ; Tanja Br&auml ; u¹ ; Florian S. Dreyer¹ ; Kirsten Kr&auml ; tzel¹ ; Jochen Dindorf¹ ; Ian C.D. Johnston³ ; Stefanie Gross¹ ; Elisabeth Kremmer⁴ ; Reinhard Zeidler⁵ ; Ursula Schlö ; tzer-Schrehardt⁶ ; Mathias Lichtenheld² ; Kalle Saksela⁷ ; Thomas Harrer⁸ ; Gerold Schuler¹ ; Maurizio Federico⁹ ; Andreas S. Baur¹ ; ² ; ^{andreas.baur@uk-erlangen.de}
• 刊名：Molecular Cell
• 出版年：2013
• 出版时间：21 February, 2013
• 年：2013
• 卷：49
• 期：4
• 页码：668-679
• 全文大小：1541 K

文摘

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Summary

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¦Á converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNF¦Á and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNF¦Á. 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.