Abstract:
: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.
journal_name
Immunityjournal_title
Immunityauthors
Simmons A,Gangadharan B,Hodges A,Sharrocks K,Prabhakar S,García A,Dwek R,Zitzmann N,McMichael Adoi
10.1016/j.immuni.2005.11.003keywords:
subject
Has Abstractpub_date
2005-12-01 00:00:00pages
621-34issue
6eissn
1074-7613issn
1097-4180pii
S1074-7613(05)00376-6journal_volume
23pub_type
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