CHIP/STUB1 suppresses the transcription and latent reactivation of HIV-1 via the TRAF6-NF-κB-HIV-LTR axis.

HIV-1 replication, transcription and latency are correlated with the activation of NF-κB signaling. C-terminus of Hsc70-interacting protein (CHIP or STUB1), a cellular E3 ligase, has been reported to inhibit Tat-mediated HIV-1 LTR promoter activity by degrading Tat. In this study, we demonstrated that CHIP modulates HIV infection by limiting viral transcription through an uncharacterized mechanism involving the negative regulation of TRAF6-NF-κB signaling. Mechanistically, CHIP targets the NF-κB signaling transducer TRAF6 but not TRAF2 or p65 for degradation via the ubiquitin-proteasome pathway, leading to the inhibition of TRAF6-mediated NF-κB signaling, which in turn suppresses NF-κB-dependent HIV-1 LTR transcription. Notably, in addition to the U-box domain, which is well known for protein degradation, the TPR domain of CHIP plays an independent role in facilitating the proteasome-mediated degradation of TRAF6 via K48-linked polyubiquitination. Furthermore, CHIP plays an inhibitory role in the reactivation of HIV-1 latency in various models, in concert with its repressive effect on the NF-κB pathway. Thus, these findings reveal that CHIP is a novel repressor of NF-κB-driven HIV-1 promoter transactivation, providing new insights into the molecular mechanisms by which upstream NF-κB signaling influences HIV-1 replication, transcription and latency.