HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals

被引:238
作者
Wolf, D
Witte, V
Laffert, B
Blume, K
Stromer, E
Trapp, S
D'Aloja, P
Schürmann, A
Baur, AS [1 ]
机构
[1] Univ Erlangen Nurnberg, Dept Dermatol Erlangen, Erlangen, Germany
[2] Rhein Westfal TH Aachen, Inst Pharmakol & Toxikol, D-5100 Aachen, Germany
关键词
D O I
10.1038/nm1101-1217
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p2l-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.
引用
收藏
页码:1217 / 1224
页数:8
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