The immune evasion protein US3 of human cytomegalovirus binds to and arrests MHC class I molecules in the endoplasmic reticulum (ER). However, substantial amounts of class I molecules still escape US3-mediated ER retention, suggesting that not all class I alleles are affected equally by US3. Here, we identify tapasin inhibition as the mechanism of MHC retention by US3. US3 directly binds tapasin and inhibits tapasin-dependent peptide loading, thereby preventing the optimization of the peptide repertoire presented by class I molecules. Due to the allelic specificity of tapasin toward class I molecules, US3 affects only class I alleles that are dependent on tapasin for peptide loading and surface expression. Accordingly, tapasin-independent class I alleles selectively escape to the cell surface.
Bibliographical noteFunding Information:
We would like to thank Drs. Peter Cresswell and Frank Momburg for providing valuable reagents. This work was supported by grants from the Molecular and Cellular BioDiscovery Research Program (M10106000054) and The Center for Functional Analysis of Human Genome (FG-3-1-01) from the Ministry of Science and Technology.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Infectious Diseases