HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases.
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 TNFα converting enzyme (TACE alias ADAM 17) and its close relative ... ADAM10. The activated proteases cleaved proTNFα and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNFα. 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.
Mesh Terms:
ADAM Proteins, Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Amyloid Precursor Protein Secretases, Case-Control Studies, Enzyme Activation, HEK293 Cells, HIV Infections, Humans, Melanoma, Membrane Microdomains, Membrane Proteins, Mutagenesis, Site-Directed, Paxillin, Phosphorylation, Polycomb Repressive Complex 2, Protein Binding, Protein Kinase C-delta, Protein Precursors, Protein Processing, Post-Translational, Protein Transport, Ribonucleoproteins, Secretory Vesicles, Signal Transduction, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases
ADAM Proteins, Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Amyloid Precursor Protein Secretases, Case-Control Studies, Enzyme Activation, HEK293 Cells, HIV Infections, Humans, Melanoma, Membrane Microdomains, Membrane Proteins, Mutagenesis, Site-Directed, Paxillin, Phosphorylation, Polycomb Repressive Complex 2, Protein Binding, Protein Kinase C-delta, Protein Precursors, Protein Processing, Post-Translational, Protein Transport, Ribonucleoproteins, Secretory Vesicles, Signal Transduction, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, nef Gene Products, Human Immunodeficiency Virus, p21-Activated Kinases
Mol. Cell
Date: Feb. 21, 2013
PubMed ID: 23317503
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