von Hippel–Lindau binding protein 1-mediated degradation of integrase affects HIV-1 gene expression at a postintegration step

Abstract

HIV-1 integrase, the viral enzyme responsible for provirus integration into the host genome, can be actively degraded by the ubiquitin-proteasome pathway. Here, we identify von HippelLindau binding protein 1(VBP1), a subunit of the prefoldin chaperone, as an integrase cellular binding protein that bridges interaction between integrase and the cullin2 (Cul2)-based von Hippel-Lindau (VHL) ubiquitin ligase. We demonstrate that VBP1 and Cul2/VHL are required for proper HIV-1 expression at a step between integrase-dependent proviral integration into the host genome and transcription of viral genes. Using both an siRNA approach and Cul2/VHL mutant cells, we show that VBP1 and the Cul2/VHL ligase cooperate in the efficient polyubiquitylation of integrase and its subsequent proteasome-mediated degradation. Results presented here support a role for integrase degradation by the prefoldin-VHL-proteasome pathway in the integrationtranscription transition of the viral replication cycle.prefoldin ͉ ubiquitin ͉ VHL ͉ retrovirus ͉ transcription

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…These findings show that oligomeric A␤ accumulation within neuronal cell bodies has pathological consequences, as proteasome impairment led to the build-up of tau protein. Another study, by Mousnier and colleagues, reported a possible prefolding-mediated proteasomal protein-degradation pathway [125]. This suggests that A␤ oligomers-prefolding complex could cause proteasome dysfunction and subsequent cell death.…”

Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation

“…hydrophobic ␤-sheets) cannot easily be changed into nontoxic forms, prefoldin probably transfers them to CCT or other appropriate chaperones. Prefoldin might also deliver misfolded toxic species to the proteasome for degradation through direct interaction (38,46).…”

Integrase, LEDGF/p75 and HIV replication

“…Establishing a clear connection between the latter effect, the INstabilizing effect of p75, and the viral cofactor role requires further investigation. In addition, a cellular protein, von Hippel Lindau binding protein 1 (VBP1), has recently been suggested to foster transition of the nascently integrated PIC to transcriptional competence by facilitating IN degradation [148]. Whether and how VBP1-mediated IN degradation intersects with p75 protection of IN [78] or with the post-strand transfer gap repair step are unknown.…”