Human cytomegalovirus (HCMV) US11 exploits Derlin-1-dependent endoplasmic reticulum-associated protein degradation (ERAD) to degrade major histocompatibility complex class I (MHC-I) molecules for immune evasion. US11 captures MHC-I molecules in the ER and convey them to Derlin-1, which then mediate their dislocation into the cytosol for degradation. The cytosolic tail of MHC-I molecules was shown to be required for dislocation to the cytosol, yet its precise role in the process remains unknown. Here, we found that the cytosolic tail of MHC-I molecules, although dispensable for interaction with US11, was required for their tight association with Derlin-1 in the presence of US11. Surprisingly, deletion of the C-terminal single amino acid of the cytosolic tail markedly disrupted the interaction between MHC-I molecules and Derlin-1, thereby rendering the mutant MHC-I molecules resistant to US11-induced degradation. Consistently, when MHC-I molecules were forced to interact with Derlin-1, through the transmembrane domain of US11 that had replaced that of the MHC-I molecules, the cytosolic tail or the C-terminal amino acid of the hybrid MHC-I became dispensable for dislocation. Thus, these results suggest that the cytosolic regions of Derlin-1 play a key role in interaction with the cytosolic tail of MHC-I molecules, and that this interaction is essential for Derlin-1 to dislocate them into the cytosol for degradation.
- Copyright © 2013 by The American Association of Immunologists, Inc.