Cytomegalovirus-induced destruction of MHC class I molecules provides insight into ER-associated protein degradation

In living cells, proteins are produced continuously. To carry out its specific functions, proteins need to be correctly folded. Proteins that are secreted or function in the cell membrane are folded in a specialized compartment in the cell, the endoplasmic reticulum (ER). The production of proteins is not free of error. To ensure that only properly folded proteins or protein complexes exit the ER to their destinations, a quality control system is in place. Proteins that are misfolded are recognized in the ER, moved from the ER into the cytosol and marked with a small protein called ubiquitin. This tag can be recognized by a large protein complex called the proteasome, which degrades the tagged misfolded protein. The ER quality control system plays an important role in diseases such as Alzheimer’s, Parkinson’s, diabetes and cystic fibrosis. Besides its importance in the disposing of misfolded proteins, the ER quality control system is also involved in the persistent infection of some viruses such as HIV and HCMV. The human cytomegalovirus (HCMV) causes a persistent infection and is present in 80% of the world population. It manifests itself mainly when the immune system is weakened, for example in AIDS patients. Normally, parts of the infecting virus are presented on the cell surface by the MHC class I complex for immune surveillance. Immune cells can recognize an infected cell and then respond by destroying both the cell and the virus within. HCMV, however, can evade detection by the immune system by targeting part of the MHC class I complex for degradation. This prevents the viral peptides from being presented on the cell surface, and thus detection. In this thesis, the degradation of MHC class I molecules is used as a model system for degradation of misfolded ER proteins. We found that the role of ubiquitin is essential in this process. Ubiquitin can be linked together to itself via internal lysine residues forming a polyubiquitin chain. We found that a specific Lys48 lined polyubiquitin chain is required for the retro-translocation of MHC class I heavy chains from the ER into the cytosol. This movement requires energy and it is likely that a protein complex recognizes the polyubiquitin chain and pulls it out of the ER membrane, before it is targeted to the proteasome for degradation. Insight in ER-associated degradation as described here may lead to the development of drugs to treat viral infections or diseases such cystic fibrosis or diabetes