title: HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases.
abstract: 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.
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, 91054 Erlangen, Germany.
authors: Jung-Hyun
authors: JH
authors: Lee
authors: Sebastian
authors: S
authors: Wittki
authors: Tanja
authors: T
authors: Bräu
authors: Florian S
authors: FS
authors: Dreyer
authors: Kirsten
authors: K
authors: Krätzel
authors: Jochen
authors: J
authors: Dindorf
authors: Ian C D
authors: IC
authors: Johnston
authors: Stefanie
authors: S
authors: Gross
authors: Elisabeth
authors: E
authors: Kremmer
authors: Reinhard
authors: R
authors: Zeidler
authors: Ursula
authors: U
authors: Schlötzer-Schrehardt
authors: Mathias
authors: M
authors: Lichtenheld
authors: Kalle
authors: K
authors: Saksela
authors: Thomas
authors: T
authors: Harrer
authors: Gerold
authors: G
authors: Schuler
authors: Maurizio
authors: M
authors: Federico
authors: Andreas S
authors: AS
authors: Baur
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D004789:Enzyme Activation; D057809:HEK293 Cells; D015658:HIV Infections / Q000097:blood / Q000201:enzymology; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D008545:Melanoma / Q000097:blood / Q000201:enzymology; D021962:Membrane Microdomains / Q000201:enzymology; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D051419:Paxillin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012261:Ribonucleoproteins / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491488:EED protein, human; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D008565:Membrane Proteins; C496061:PXN protein, human; D051419:Paxillin; D011498:Protein Precursors; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C072074:HNRNPK protein, human; D063151:Polycomb Repressive Complex 2; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D054462:p21-Activated Kinases; D051745:Protein Kinase C-delta; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human