Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.immuni.2005.11.003

Type

Journal article

Journal

Immunity

Publication Date

12/2005

Volume

23

Pages

621 - 634

Keywords

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