Degrading our defenses: novel features of human cytomegalovirus-induced HLA class I ERADication

Abstract

Herpesviruses have evolved various strategies to evade the immune system of their hosts. As a member of the Herpesviridae, human cytomegalovirus (HCMV) evades immune recognition by specifically downregulating antigen-presenting HLA class I molecules. During its synthesis, HLA class I is translocated into the endoplasmic reticulum (ER), where it is loaded with an antigenic peptide. Once loaded with a peptide, the HLA class I complex travels to the plasma membrane, where it can activate CD8+ T cells. The HCMV proteins US2 and US11 prevent this by degrading ER-resident HLA class I molecules, hijacking the quality control mechanism for misfolded proteins. In this process, called ER-associated protein degradation (ERAD), misfolded proteins are recognized in the ER and transported back into the cytosol, where they are degraded by the ubiquitin-proteasome system. The mechanisms of ERAD are complex and only partially understood. With US2- and US11-mediated HLA class I degradation as a model for ERAD, we have screened for and functionally characterized novel components of ER-associated HLA class I degradation.