HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases
HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases
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DOI：
10.1016/j.molcel.2012.12.004
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发表时间：
2013-02-21
期刊：
影响因子：
16
通讯作者：
Baur, Andreas S.
中科院分区：
文献类型：
--
作者：
Lee, Jung-Hyun;Wittki, Sebastian;Baur, Andreas S.
HIV Nef蛋白招募多梳蛋白Eed并模拟整联蛋白受体信号，原因尚不完全清楚。在这里，我们证明了Nef和Eed与整合素效应物桩蛋白复合物募集和激活TNF α转化酶（TACE别名ADAM 17）及其近亲ADAM 10。活化的蛋白酶切割proTNF α并穿梭进入细胞外囊泡（EV）。摄入这些EV的外周血单核细胞释放TNF α。分析其机制，我们发现Pak 2，一种已建立的Nef的宿主细胞效应器，磷酸化Ser 272/274上的桩蛋白，以诱导TACE-桩蛋白缔合并通过脂筏穿梭进入EV。相反，Pak 1磷酸化桩蛋白Ser 258，抑制TACE协会和脂筏转移。有趣的是，黑色素瘤细胞使用相同的机制主要将ADAM 10穿梭到EV中。我们的结论是，HIV-1和癌细胞利用桩蛋白/整合素控制的机制释放TACE/ADAM 10含有囊泡，确保更好的增殖/生长条件，在他们的微环境。
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.