Abstract

As the ultimate intracellular parasites, viruses target the host cellular machinery to enable their replication and avoid elimination by the immune system. We have taken functional genetic and proteomic approaches to identify novel cellular receptors manipulated by viruses, understand why these receptors are affected and to elucidate the mechanisms viruses use to manipulate their cellular targets.

Our work on viral evasion of the MHC class I antigen presentation pathway has driven an interest in the role of ubiquitin in immunoreceptor regulation. For example, the K3 and K5 virally encoded ubiquitin E3 ligases recruit host E2 enzymes to ubiquitinate MHC class I molecules. These lys63-linked ubiquitin conjugates initiate the downregulation and subsequent endolysosomal degradation of cell surface MHC I molecules.

However, a large number of cell surface receptors will be modulated by different intracellular pathogens. We therefore developed an unbiased proteomics approach to identify those receptors whose expression at the cell surface is altered upon viral infection. Using SILAC -based proteomics, the identification and differential analysis of >600 plasma membrane proteins allows us to find those receptors downregulated by viruses.

This approach has identified immune evasion as well as metabolic receptors whose expression is dramatically altered following infection, and will be discussed during the seminar.