Functional Characterization of the Multi-domain Herpesvirus Essential Tegument Protein VP1/2: At the Core of Infectious ProcessesPublic Deposited
The neurotropic alphaherpesviruses infect and spread trans-synaptically within the vertebrate nervous system. Recurrent diseases are often manifested at the periphery of the host organism but occasional dissemination of the virus to the brain results in fatal encephalitis. Interactions between viral and host cellular proteins are integral to the success of a life-long infection. While inside the host cell, the most accessible viral component may include the DNA-enclosing capsid and the tegument layer, a collection of ~15 proteins that mediate a wide range of functions. This dissertation work investigates the largest virally encoded protein within the tegument, VP1/2, which is essential for viral propagation. A VP1/2-null virus was used to first establish the importance of VP1/2 in capsid intracellular transport during infection. A domain-specific mutational analysis was then used to correlate essential functions to VP1/2 regions. We find that the amino terminus of VP1/2, encompassing the deubiquitinase activity, is not essential for viral propagation but required for neuroinvasion. The carboxy terminus of VP1/2 can exist as a cleaved form to function independently of the full-length protein to mediate capsid nuclear egress. The direct interaction of VP1/2 with capsid proteins, both cytoplasmic and nuclear, was examined and the binding domain identified. In all, this work unravels the very large, essential tegument protein VP1/2 to reveal novel functions of its multiple domains.