Degrading our defenses

Novel features of human cytomegalovirus-induced HLA class I ERADication

Anouk Schuren

Promoter:
Prof.dr. E.J.H.J. (Emmanuel) Wiertz
Co-promoter:
Dr. R.J. (Robert Jan) Lebbink
Date:
April 2, 2019
Time:
14:30 h

Summary

Herpesviruses have evolved various strategies to evade the immune system of their hosts. As a member of the Herpesviridae, human cytomegalovirus (HCMV) evades immune recognition by specifically downregulating antigen-presenting HLA class I molecules. During its synthesis, HLA class I is translocated into the endoplasmic reticulum (ER), where it is loaded with an antigenic peptide. Once loaded with a peptide, the HLA class I complex travels to the plasma membrane, where it can activate CD8+ T cells. The HCMV proteins US2 and US11 prevent this by degrading ER-resident HLA class I molecules, hijacking the quality control mechanism for misfolded proteins. In this process, called ER-associated protein degradation (ERAD), misfolded proteins are recognized in the ER and transported back into the cytosol, where they are degraded by the ubiquitin-proteasome system.

The mechanisms of ERAD are complex and only partially understood. With US2- and US11-mediated HLA class I degradation as a model for ERAD, we have screened for and functionally characterized novel components of ER-associated HLA class I degradation. 

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