The human immunodeficiency virus type 1 Vpu protein inhibits NF-kappa B activation by interfering with beta TrCP-mediated degradation of Ikappa B.
The human immunodeficiency virus type 1 (HIV-1) Vpu protein binds to the CD4 receptor and induces its degradation by cytosolic proteasomes. This process involves the recruitment of human betaTrCP (TrCP), a key member of the SkpI-Cdc53-F-box E3 ubiquitin ligase complex that specifically interacts with phosphorylated Vpu molecules. Interestingly, Vpu itself, unlike other TrCP-interacting proteins, is not targeted for degradation by proteasomes. We now report that, by virtue of its affinity for TrCP and resistance to degradation, Vpu, but not a phosphorylation mutant unable to interact with TrCP, has a dominant negative effect on TrCP function. As a consequence, expression of Vpu in HIV-infected T cells or in HeLa cells inhibited TNF-alpha-induced degradation of IkappaB-alpha. Vpu did not inhibit TNF-alpha-mediated activation of the IkappaB kinase but instead interfered with the subsequent TrCP-dependent degradation of phosphorylated IkappaB-alpha. This resulted in a pronounced reduction of NF-kappaB activity. We also observed that in cells producing Vpu-defective virus, NF-kappaB activity was significantly increased even in the absence of cytokine stimulation. However, in the presence of Vpu, this HIV-mediated NF-kappaB activation was markedly reduced. These results suggest that Vpu modulates both virus- and cytokine-induced activation of NF-kappaB in HIV-1-infected cells.
Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, USA.
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Bour
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Perrin
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Akari
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Strebel
D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016338:Genes, vpu; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins; D000086082:Viroporin Proteins
D015704:CD4 Antigens; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D019204:GTP-Binding Proteins; D054298:Human Immunodeficiency Virus Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins; D013752:Tetracycline; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C471644:BTRC protein, human; C000606204:NFKBIA protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins