THE HUMAN CYTOMEGALOVIRUS US11 GENE-PRODUCT DISLOCATES MHC CLASS-I HEAVY-CHAINS FROM THE ENDOPLASMIC-RETICULUM TO THE CYTOSOL

Human cytomegalovirus (HCMV) down-regulates expression of MHC class I products by selective proteolysis. A single HCMV gene, US11, which enc odes an endoplasmic reticulum (ER) resident type-I transmembrane glyco protein, is sufficient to cause this effect. In US11(+) cells, MHC cla ss I molecules are core-glycosylated and therefore inserted into the E R. They are degraded with a half-time of less than 1 min. A full-lengt h breakdown intermediate that has lost the single N-linked glycan in a n N-glycanase-catalyzed reaction transiently accumulates in cells expo sed to the protease inhibitors LLnL, Cbz-LLL, and lactacystin, identif ying the proteasome as a key protease. Subcellular fractionation exper iments show this intermediate to be cytosolic. Thus, US11 dislocates n ewly synthesized class I molecules from the ER to the cytosol, where t hey are acted upon by an N-glycanase and the proteasome.