Open AccessStructural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses
Author(s) -
Sofia Banchenko,
Ferdinand Krupp,
Christine Gotthold,
Jörg Bürger,
Andrea Graziadei,
Francis J. O’Reilly,
Ludwig Sinn,
Olga Ruda,
Juri Rappsilber,
C.M.T. Spahn,
Thorsten Mielke,
Ian A. Taylor,
David Schwefel
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009775
Subject(s) - samhd1 , simian immunodeficiency virus , biology , ubiquitin ligase , ubiquitin , microbiology and biotechnology , cullin , viral replication , virology , virus , genetics , gene , reverse transcriptase , rna
Viruses have evolved means to manipulate the host’s ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4 DCAF1 specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infecting Cercopithecus cephus (SIV mus ). X-ray crystallography reveals commonalities between SIV mus Vpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIV mus Vpr exploits the dynamic architecture of the multi-subunit CRL4 DCAF1 assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.