Abstract
Human immunodeficiency virus (HIV) type 1 Vpu is an integral membrane protein with a unique affinity for betaTrCP (TrCP), a key member of the SkpI-Cullin-F-box E3 ubiquitin ligase complex that is involved in the regulated degradation of cellular proteins, including IkappaB. Remarkably, Vpu is resistant to TrCP-mediated degradation and competitively inhibits TrCP-dependent degradation of IkappaB, resulting in the suppression of nuclear factor (NF)-kappaB activity in Vpu-expressing cells. We now report that Vpu, through its interaction with TrCP, potently contributes to the induction of apoptosis in HIV-infected T cells. Vpu-induced apoptosis is specific and independent of other viral proteins. Mutation of a TrCP-binding motif in Vpu abolishes its apoptogenic property, demonstrating a close correlation between this property of Vpu and its ability to inhibit NF-kappaB activity. The involvement of NF-kappaB in Vpu-induced apoptosis is further supported by the finding that the levels of antiapoptotic factors Bcl-xL, A1/Bfl-1, and TNF receptor-associated factor (TRAF)1, all of which are expressed in an NF-kappaB-dependent manner, are reduced and, at the same time, levels of active caspase-3 are elevated. Thus, Vpu induces apoptosis through activation of the caspase pathway by way of inhibiting the NF-kappaB-dependent expression of antiapoptotic genes.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis*
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Binding Sites
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CD4 Antigens / genetics
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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Caspase 3
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Caspases / metabolism
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Cell Line, Transformed
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Enzyme Activation
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GTP-Binding Proteins / metabolism
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Gene Expression
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Gene Products, env / metabolism
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HIV-1 / metabolism*
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HIV-1 / physiology
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HeLa Cells
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Human Immunodeficiency Virus Proteins
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Humans
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Jurkat Cells
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Minor Histocompatibility Antigens
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NF-kappa B / metabolism*
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Peptide Synthases / metabolism
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Protein Biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Recombinant Fusion Proteins / genetics
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SKP Cullin F-Box Protein Ligases
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TNF Receptor-Associated Factor 1
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Tumor Necrosis Factor-alpha / pharmacology
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Viral Regulatory and Accessory Proteins / genetics
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Viral Regulatory and Accessory Proteins / metabolism*
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Viral Regulatory and Accessory Proteins / physiology
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bcl-X Protein
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beta-Transducin Repeat-Containing Proteins
Substances
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BCL2-related protein A1
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BCL2L1 protein, human
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BTRC protein, human
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CD4 Antigens
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Gene Products, env
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Human Immunodeficiency Virus Proteins
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Minor Histocompatibility Antigens
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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TNF Receptor-Associated Factor 1
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Tumor Necrosis Factor-alpha
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Viral Regulatory and Accessory Proteins
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bcl-X Protein
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beta-Transducin Repeat-Containing Proteins
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vpu protein, Human immunodeficiency virus 1
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SKP Cullin F-Box Protein Ligases
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CASP3 protein, human
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Caspase 3
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Caspases
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GTP-Binding Proteins
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Peptide Synthases