DISLOCATION OF TYPE-I MEMBRANE-PROTEINS FROM THE ER TO THE CYTOSOL ISSENSITIVE TO CHANGES IN REDOX POTENTIAL

The human cytomegalovirus (HCMV) gene products US2 and US11 dislocate major histocompatibility class I heavy chains from the ER and target t hem for proteasomal degradation in the cytosol. The dislocation reacti on is inhibited by agents that affect intracellular redox potential an d/or free thiol status, such as diamide and N-ethylmaleimide. Subcellu lar fractionation experiments indicate that this inhibition occurs at the stage of discharge from the ER into the cytosol. The T cell recept or or (TCR alpha) chain is also degraded by a similar set of reactions , yet in a manner independent of virally encoded gene products. Diamid e and N-ethylmaleimide likewise inhibit the dislocation of the full-le ngth TCR alpha chain from the ER, as well as a truncated, mutant versi on of TCR alpha chain that lacks cysteine residues. Cytosolic destruct ion of glycosylated, ER-resident type I membrane proteins, therefore, requires maintenance of a proper redox potential for the initial step of removal of the substrate from the ER environment.