HCMV US2 co-opts TRC8 to degrade the ER-resident protein LMAN2L

The human cytomegalovirus (HCMV) pUS2 glycoprotein exploits the host’s endoplasmic reticulum (ER)-associated degradation (ERAD) pathway to degrade MHC class I and prevent antigen presentation. Beyond MHC class I, pUS2 has been shown to target a range of cellular proteins for degradation, preventing their cell surface expression. Here we have identified a novel pUS2 target, ER-resident protein lectin mannose binding 2 like (LMAN2L). pUS2 expression was both necessary and sufficient for the downregulation of LMAN2L, which was dependent on the cellular E3 ligase TRC8. Given the hypothesised role of LMAN2L in the trafficking of glycoproteins, we employed proteomic plasma membrane profiling to measure LMAN2L-dependent changes at the cell surface. Known pUS2 target integrin alpha-6 (ITGA6) was downregulated from the surface of LMAN2L deficient cells. Overall, these results suggest a novelstrategy of pUS2-mediated protein degradation whereby pUS2 targets LMAN2L to impair trafficking of ITGA6. Given US2 can directly target other integrins, this single viral protein exhibits both direct and indirect mechanisms to downregulate integrins from the cell surface.