PHD3-VHL axis controls HIV-2 infection through oxygen-dependent hydroxylation and degradation of Vpx.

ABSTRACT: HIV-2 viral protein X (Vpx) plays a pivotal role in antagonizing the host restriction factors, including SAMHD1 and components of the HUSH complex, to facilitate viral replication. However, the regulatory mechanisms controlling Vpx stability remain unclear. In this study, we identify the von Hippel-Lindau (VHL) tumor suppressor as a novel E3 ubiquitin ligase that specifically targets Vpx for proteasomal degradation. Mechanistically, we demonstrate that VHL-mediated degradation depends on the oxygen-dependent hydroxylation of Vpx at proline residue 41 (Pro41), a modification catalyzed by prolyl hydroxylase domain-containing protein 3 (PHD3). Using an integrated approach combining crosslinking mass spectrometry and molecular modeling analyses, we elucidate the structural architecture of the

SUBMITTER: Miyakawa K 

PROVIDER: S-EPMC12201638 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature