The role of proteasomes in the ERADication of MHC class I by HCMV US2 and US11

Abstract

Herpesviruses have developed powerful immune evasion strategies leading to lifelong persistence of the virus, although strong immune responses are present. Viral immune evasion proteins, including several proteins of human cytomegalovirus (HCMV), interfere with the MHC I presentation pathway at almost every step to prevent recognition by cytotoxic T cells. In particular, HCMV US2 and US11 are very effective in inducing rapid dislocation and degradation of MHC I. Because of this clear phenotype, US2- and US11-induced MHC I degradation has often been used to study ER-associated degradation (ERAD). The main steps in the ERAD pathway are substrate recognition, targeting of substrates to membrane-bound E3 ligases, dislocation into the cytosol and degradation by the proteasome. Studying the mechanisms of US2- and US11-induced dislocation and degradation of MHC I has led to the identification of many components of ERAD and a better understanding of general ERAD mechanisms. Our understanding of the mechanisms of US2 and US11 has also greatly increased. US2 and US11 both use distinct membrane complexes and pathways for the induction of MHC I dislocation and degradation. Proteasomes are essential for the degradation of ERAD substrates. Furthermore, there is convincing data arguing that proteasomes are involved in the dislocation of, at least some, ERAD substrates. Via the AAA-ATPase subunits of the proteasome a direct pulling force could be exerted on substrates but proteasomes could also be involved in another way. Increasing our understanding of the different ERAD pathways will ultimately lead to targeting these pathways for the treatment of HCMV infection and other ERAD-associated diseases.