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Peptide-based Identification of Functional Motifs and their Binding Partners
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Peptide-based Identification of Functional Motifs and their Binding Partners

Published on: July 1, 2013

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

D Wolf1, V Witte, B Laffert

  • 1Department of Dermatology Erlangen, University of Erlangen/Nürnberg, Erlangen, Germany.

Nature Medicine
|November 2, 2001
PubMed

Insights

Human immunodeficiency virus (HIV) Nef proteins block T cell apoptosis by activating a phosphatidylinositol 3-kinase-PAK complex. This mechanism is crucial for viral replication and AIDS pathogenesis.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Nef proteins from human or simian immunodeficiency viruses possess a conserved signaling property involving p21-activated kinase (PAK) activation.
  • The precise function of PAK activation by Nef remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of Nef-mediated PAK activation.
  • To investigate the role of Nef-induced PAK activation in cellular apoptosis and viral pathogenesis.

Main Methods:

  • Investigated the interaction between Nef, phosphatidylinositol 3-kinase (PI3K), and PAK.
  • Analyzed the phosphorylation of the pro-apoptotic Bad protein by the Nef-PI3K-PAK complex.
  • Assessed the effect of Nef and its mutants on T cell apoptosis induced by serum starvation or HIV replication.

Main Results:

  • Nef-mediated PAK activation involves PI3K, which acts upstream of PAK and is activated by Nef.
  • The Nef-associated PI3K-PAK complex phosphorylates the pro-apoptotic Bad protein, independent of Akt kinase.
  • Nef, but not a PAK-inactive mutant, effectively blocked apoptosis in T cells.

Conclusions:

  • Nef utilizes a PI3K-PAK signaling pathway to phosphorylate Bad, inhibiting apoptosis.
  • This anti-apoptotic effect mediated by Nef is critical for viral replication and contributes to AIDS pathogenesis.

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