Role of Deubiquitinases in CMV Pathogenesis

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Project Summary/Abstract All viruses must navigate the cellular ubiquitin (Ub) system en route to successful infection. Ubiquitin is a versatile posttranslational modification controlling many diverse cellular processes, from protein quality control, trafficking and degradation to signal transduction pathways. Activation of sequential E1-E2-E3 Ub-ligase cascades result in covalent attachment of one or more Ub molecules to lysine residues in substrate proteins. Arrays of different Ub-Ub linkages, in large part, dictate the regulatory role of Ub modification on the stability, localization, or function of target proteins. Conversely, Ub can be removed from modified proteins to reverse its effects through the activities of numerous deubiquitinating enzymes (DUBs). All herpesviruses encode DUBs that are implicated in facilitating the viral life cycle; however, a thorough understanding of the activity, specificity, and biology of these viral DUBs during a natural infection remains incomplete. We have previously shown that the conserved DUB encoded by the murine cytomegalovirus (MCMV) controls inflammation and viral pathogenesis during infection in a natural host. It does so by regulating the host ER-associated degradation (ERAD) and other pathways, to control the expression and secretion of a critical viral chemokine. The objective of this research plan is to determine the molecular mechanisms by which MCMV DUB facilitates pathogenesis during infection in a natural host. Our preliminary data lead to the overall hypothesis that MCMV DUB activity targets both host and viral factors to evade innate immune responses and facilitate viral infection. This hypothesis will be tested by pursuing two specific aims: 1) determine the mechanisms of CMV DUB activity regulating host ERAD and protein trafficking pathways during infection and 2) determine the linkage specificity target substrates of the MCMV DUB in vitro and during infection. These efforts will yield significant mechanistic insight into the complex and novel role CMV deubiquitinases play in pathogenesis and host responses, and underscore the potential utility of targeting DUB functions to combat viral infections.