Molecular cell biology of MHC class I retention by the gp40 protein of the murine cytomegalovirus

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MHC (major histocompatibility complex) class I molecules play a key role in the anti-viral immune response by presenting viral antigens to cytotoxic T lymphocytes at the cell surface, which leads to apoptosis of the infected cell and to the control of infection. It is therefore not astonishing that many viruses have developed strategies to circumvent recognition by MHC class I molecules in order to persist: A vast number of viral proteins exist that interfere with antigen presentation, the so-called immunoevasins. We have been studying the immunoevasin gp40 of the murine cytomegalovirus (MCMV) and found out that its mode of action differs from that one of other immunoevasins: It binds to MHC class I molecules but, unlike other immunoevasins that interact directly, it does not lead to their degradation, instead, fully mature class I molecule are retained in an early compartment of the secretory pathway unable to reach the cell surface. We have further identified a novel sequence in gp40, the linker, which is required for both its own retention and that one of MHC class I molecules. These data are already summarized in a manuscript and will be submitted to publication soon. In this project, we will investigate the prerequisite for gp40-mediated class I intracellular retention, namely, the intracellular retention of gp40 itself: We will describe the kind of retention taking place, determine the function of the linker sequence in the retention process, and identify potential binding partners of gp40 that might regulate gp40 retention and, hence, its function. We will also investigate in detail the interaction between gp40 and class I in live cells. A more profound understanding of gp40 retention will help to shed light on the diversity of viral immune evasion strategies that are responsible for lifelong viral persistence.