Grant: CIHR Fellowship

Up to 80% of the global population is infected with herpes simplex virus (HSV), which can cause a range of illnesses from cold sores to life threatening inflammation of the central nervous system. A hallmark of HSV is the ability to enter a latent state of infection. With no cure or vaccine available, HSV infection remains lifelong. Central to HSV infection, and many other viruses, is hijacking of the cellular ubiquitination machinery. Ubiquitination occurs via a stepwise reaction of E1 activating, E2 conjugating, and E3 ubiquitin ligase enzymes, and can alter protein function or direct their degradation. Herpes simplex virus (HSV) encodes the viral E3 ubiquitin ligase ICP0, which is important for viral transcription, reactivation from latency, and counteracting immune responses. ICP0 redirects ubiquitination of host proteins and targets host antiviral factors for degradation. Currently, our understanding of ICP0 substrates and interactors does not fully explain ICP0 functions. A central challenge in studying ubiquitin biology is the identification of direct E3 ligase targets. In the context of infection, differentiating between direct (viral) and indirect (cellular) ubiquitination of host proteins adds additional complexity. Understanding the relationship between E3s and their targets is essential to our understanding of the biological pathways they effect, or hijack in the context of infection. I propose that HSV ICP0 can serve as a general model to develop approaches addressing these challenges and generate a complete picture of E3-mediated ubiquitination though integration of diverse data types. This will elucidate biologically relevant virus-host interactions and will inform our understanding of cellular ubiquitination mechanisms and ICP0 biology. This new knowledge can be used to develop antiviral therapeutics targeting HSV.