Professor Richard Roller, PhD, has successfully renewed his R21 grant entitled, "Mechanism and regulation of protein kinase functions in HSV nuclear egress" from the National Institute of Health (NIH).

Abstract

Alphaherpesviruses encode two proteins kinases that are critical regulators of pathogenesis, pUS3 and pUL13. pUS3 has multiple functions in infection including facilitation of nuclear egress, protection from apoptosis, promotion of viral protein synthesis, and inhibition of antigen presentation to the immune system. The regulation of the activity of pUS3 is, therefore, of great interest, both as a tool for understanding the molecular biology of herpesvirus infections, and as an avenue for exploring antiviral therapies based on inhibition of its various activities. pUS3 kinase activity has been reported to be regulated both by autophosphorylation and by phosphorylation by another herpesvirus-encoded kinase, pUL13. Intriguingly, regulation of pUS3 activity by pUL13 appears to affect some pUS3 functions, but not others. Specifically, it appears to be necessary for at least some of the activities of pUS3 in egress of virus capsids from the nucleus, but not for protection of infected cells from some pro-apoptotic stimuli (). These observations highlight two very significant gaps in our understanding of the interaction between pUL13 and pUS3. First, it is unclear which pUS3 functions are regulated by pUL13, and what distinguished UL13-dependent from UL13-independent functions. We propose the simple hypothesis that phosphorylation of pUS3 by pUL13 specifically regulates its nuclear functions by regulating its access to the nucleus. Second, the mechanism and functional significance of pUL13 regulation of pUS3 is unclear. It is known that pUL13 phosphorylates pUS3, but it is not clear whether this phosphorylation is necessary for pUL13 regulation of pUS3. A recently published proteomic analysis of HSV infected cells suggests that pUL13 phosphorylates pUS3 at S139. We will use a genetic approach to test the hypothesis that S139 is the critical residue for regulation of pUS3 by pUL13, and then to test the significance of S139 phosphorylation for viral growth and spread.