The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors

J Exp Med. 2001 Nov 5;194(9):1299-311. doi: 10.1084/jem.194.9.1299.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Binding Sites
  • CD4 Antigens / genetics
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Transformed
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • Gene Expression
  • Gene Products, env / metabolism
  • HIV-1 / metabolism*
  • HIV-1 / physiology
  • HeLa Cells
  • Human Immunodeficiency Virus Proteins
  • Humans
  • Jurkat Cells
  • Minor Histocompatibility Antigens
  • NF-kappa B / metabolism*
  • Peptide Synthases / metabolism
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Recombinant Fusion Proteins / genetics
  • SKP Cullin F-Box Protein Ligases
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha / pharmacology
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / metabolism*
  • Viral Regulatory and Accessory Proteins / physiology
  • bcl-X Protein
  • beta-Transducin Repeat-Containing Proteins

Substances

  • BCL2-related protein A1
  • BCL2L1 protein, human
  • BTRC protein, human
  • CD4 Antigens
  • Gene Products, env
  • Human Immunodeficiency Virus Proteins
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha
  • Viral Regulatory and Accessory Proteins
  • bcl-X Protein
  • beta-Transducin Repeat-Containing Proteins
  • vpu protein, Human immunodeficiency virus 1
  • SKP Cullin F-Box Protein Ligases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • GTP-Binding Proteins
  • Peptide Synthases