HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals.
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 p21-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.
Wolf
D
D
Department of Dermatology Erlangen, University of Erlangen/Nürnberg, Erlangen, Germany.
Witte
V
V
Laffert
B
B
Blume
K
K
Stromer
E
E
Trapp
S
S
d'Aloja
P
P
Schürmann
A
A
Baur
A S
AS
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D015693:Gene Products, nef / Q000502:physiology*; D015754:Genes, nef; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014162:Transfection; D014779:Virus Replication; D051025:bcl-Associated Death Protein; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases
D002352:Carrier Proteins; D015693:Gene Products, nef; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051025:bcl-Associated Death Protein; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases; C494819:BAD protein, human; C494820:Bad protein, mouse; C494918:AKT1 protein, human