A molecular understanding of how the immunomodulatory E3-19K protein from adenovirus interferes with the class I antigen presentation pathway (78.13)

Abstract

Abstract Adenoviruses (Ads) cause persistent infections. The Ad E3-19K protein binds and retains class I MHC molecules in the endoplasmic reticulum (ER), suppressing the cell-surface presentation of viral peptides. The molecular mechanism of E3-19K-mediated class I retention is mostly uncharacterized. This knowledge is important to better understand Ad pathogenicity, and to gain insights into the susceptibility of the class I antigen presentation pathway to viral interferences. Using biophysical and cell-based approaches, we showed for the first time that E3-19K associates with immature (nascent) and mature (peptide-filled) class I molecules. We also showed that E3-19K does not compete with the class I assembly proteins for binding onto class I molecules. Importantly, immature class I sequestered by E3-19K can still bind peptides. Together, these results suggest that Ads have evolved to interfere with the early and late stages of the class I antigen presentation pathway. We also showed that E3-19K associates with HLA-A and -B molecules, but not HLA-C molecules. This locus specificity may provide a functional advantage to Ads by inactivating T-cell receptors, while avoiding activation of NK receptors. Finally, we showed that residue 56 in MHC and residue 93 in E3-19K are highly critical for class I association with E3-19K. Overall, our results provide a molecular understanding of Ad pathogenicity. Funded by NIH AI65943.