Induction of HIV Transcription by Nef Involves Lck Activation and Protein Kinase Cθ Raft Recruitment Leading to Activation of ERK1/2 but Not NFκB

Abstract

The Nef protein of HIV-1 is a key promoter of disease progression, owing to its dramatic yet ill-defined impact on viral replication. Previously, we have shown that Nef enhances Tat-mediated transcription in a manner depending on Lck and the cytoplasmic sequestration of the transcriptional repressor embryonic ectodermal development [corrected]. In this study, we report that Lck is activated by Nef and targets protein kinase Ctheta downstream, leading to the translocation of the kinase into membrane microdomains. Although microdomain-localized protein kinase Ctheta is thought to induce the transcription factor NFkappaB, we unexpectedly failed to correlate Nef-induced signaling events with enhanced NFkappaB activity. Instead, we observed an increase in ERK MAPK activity. We conclude that Nef-mediated signaling cooperates with Nef-induced derepression and supports HIV transcription through an ERK MAPK-dependent, but NFkappaB-independent, pathway.