The viral response to cellular antiviral defenses is a key step that determines the outcome of viral infection and pathogenesis. Although this has been extensively studied in other viruses, less is known about how herpes simplex viruses (HSV) modulate cellular antiviral defenses. It has been established that virus infection activates the double-stranded RNA dependent protein kinase (PKR), which phosphorylates the alpha subunit of translation initiation factor 2 (eIF-2alpha), leading to the shutoff of protein synthesis and the inhibition of viral replication. In HSV infected cells the gamma134.5 protein is required to block the shutoff of protein synthesis and this function maps to the carboxyl terminal domain. It is believed that the gamma134.5 protein and protein phosphatase 1 (PP1), in association with additional components, form a functional multi-protein complex that dephosphorylates eIF-2alpha and prevents shutoff of protein synthesis. Thus, HSV appears to use a novel strategy to escape host antiviral response that is different from those used by other viruses. The long-term objective of this research is to understand the molecular mechanism of HSV pathogenesis. Current efforts are focused on the role of the gamma134.5 protein. The specific goals are: (1) To define the minimal functional module of the gamma134.5 protein by deletion analysis. (2) To characterize the PP 1 binding domain and define the role of the putative effector domain of the gamma134.5 protein by deletions or site-specific mutations. (3) To examine the molecular nature of interactions between eIF-2alpha, PP1 and the gamma134.5 protein by analysis of the gamma134.5-PP1 complex in vitro and in virus infected cells. These studies should provide insights into HSV infection that could result in the development of novel therapeutic agents. Since the carboxyl terminus of the gamma134.5 protein can be functionally substituted by the corresponding homologous domain of the cellular protein GADD34/MyD116, these studies may also shed light on cell growth control.
| Verpooten, Dustin; Ma, Yijie; Hou, Songwang et al. (2009) Control of TANK-binding kinase 1-mediated signaling by the gamma(1)34.5 protein of herpes simplex virus 1. J Biol Chem 284:1097-105 |
| Jin, Huali; Ma, Yijie; Prabhakar, Bellur S et al. (2009) The gamma 1 34.5 protein of herpes simplex virus 1 is required to interfere with dendritic cell maturation during productive infection. J Virol 83:4984-94 |
