The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors.
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.
Akari
H
H
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Bour
S
S
Kao
S
S
Adachi
A
A
Strebel
K
K
D017209:Apoptosis; D001665:Binding Sites; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D015686:Gene Products, env / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D019169:Jurkat Cells; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism*; D010453:Peptide Synthases / Q000378:metabolism; D014176:Protein Biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051020:bcl-X Protein; D044844:beta-Transducin Repeat-Containing Proteins; D000086082:Viroporin Proteins
D015704:CD4 Antigens; D053148:Caspase 3; D020169:Caspases; D019204:GTP-Binding Proteins; D015686:Gene Products, env; D054298:Human Immunodeficiency Virus Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D010453:Peptide Synthases; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D044843:SKP Cullin F-Box Protein Ligases; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; D051020:bcl-X Protein; D044844:beta-Transducin Repeat-Containing Proteins; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; C471644:BTRC protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C505407:CASP3 protein, human