Determinants of lentiviral Vpx-CRL4 E3 ligase-mediated SAMHD1 degradation in the substrate adaptor protein DCAF1.

Determinants of lentiviral Vpx-CRL4 E3 ligase-mediated SAMHD1 degradation in the substrate adaptor protein DCAF1.
Biochem Biophys Res Commun. 2019 Apr 17;:
Authors: Guo H, Zhang N, Shen S, Yu XF, Wei W
Abstract
The lentiviral accessory protein Vpx enhances viral replication in macrophages, dendritic cells and resting CD4+ T cells by utilizing the host CRL4-DCAF1 E3 ligase to trigger the degradation of the intrinsic antiviral factor SAMHD1. Distinct from the species-specific recognition of either the N or C-terminus of SAMHD1 by Vpx proteins of different HIV-2 and SIV lineages, Vpx recruits SAMHD1 onto the same CRL4-DCAF1 complex. However, the determinants in DCAF1 that are required for Vpx-mediated SAMHD1 degradation have not been well characterized. Here, we demonstrate that the viral protein Vpx is resistant to suppression by a cellular inhibitor of the CRL4-DCAF1 E3 ligase, Merlin/NF2, through targeting a separate binding region in DCAF1. The Merlin binding-deficient DCAF1 truncation mutant (1-1417) is sufficient for Vpx-CRL4-DCAF1 E3 ligase assembly and SAMHD1 degradation. We found that the carboxyl-terminus ED-rich region (1312-1417) of DCAF1 is required for the nuclear localization of DCAF1 and for the Vpx-DCAF1 interaction. We identified the DCAF1 (1-1311) truncation mutant as a dominant negative mutant of wild-type DCAF1 that inhibits Vpx-mediated SAMHD1 degradation. These results suggest a unique strategy by which Vpx exploi...

Source: Biochemical and Biophysical Research communications - April 16, 2019 Category: Biochemistry Authors: Guo H, Zhang N, Shen S, Yu XF, Wei W Tags: Biochem Biophys Res Commun Source Type: research