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Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling.

Lentiviral Nef increases T cell signaling activity, but the molecular nature of the stimulus involved is incompletely described. We explored CD4 T cell lipid raft composition in the presence and absence of Nef. Here, the E2 ubiquitin-conjugating enzyme UbcH7, which acts in conjunction with c-Cbl, is absent from lipid rafts. This Nef-mediated exclusion is associated with failure of ubiquitination of activated Vav. In the presence of Nef, lipid raft Cdc42 is activated and forms a ternary complex between the c-Cbl-interacting protein p85Cool-1/betaPix and c-Cbl, displacing UbcH7 from rafts. Suppression of p85Cool-1/betaPix expression restores UbcH7 raft localization and Vav ubiquitination and diminishes Cdc42 activity. Moreover, p85Cool-1/betaPix knockdown attenuates HIV replication. Thresholds for activation of signaling involve the intricate balance of positive and negative regulators. Here we provide evidence for Nef disruption of a negative regulator of T cell signaling in promoting HIV replication.

Pubmed ID: 16356860


  • Simmons A
  • Gangadharan B
  • Hodges A
  • Sharrocks K
  • Prabhakar S
  • GarcĂ­a A
  • Dwek R
  • Zitzmann N
  • McMichael A



Publication Data

December 16, 2005

Associated Grants


Mesh Terms

  • Blotting, Western
  • CD4-Positive T-Lymphocytes
  • Cell Cycle Proteins
  • Cell Line
  • Enzyme-Linked Immunosorbent Assay
  • Gene Products, nef
  • Guanine Nucleotide Exchange Factors
  • HIV
  • Humans
  • Immunoprecipitation
  • Membrane Microdomains
  • Microscopy, Confocal
  • Proto-Oncogene Proteins c-cbl
  • RNA, Small Interfering
  • Rho Guanine Nucleotide Exchange Factors
  • Signal Transduction
  • Ubiquitin-Conjugating Enzymes
  • Virus Replication
  • cdc42 GTP-Binding Protein
  • nef Gene Products, Human Immunodeficiency Virus