Using herpes simplex virus as a tool to interrogate fundamental cellular stress pathways.

点击翻译按钮获取中文摘要

Studies of how viruses interact with host cells have led to the discovery of many conserved host processes. Indeed, viruses such as Herpes simplex virus (HSV) have co-evolved with humans for thousands of years, thus HSV is an excellent tool to study host functions. An emerging new paradigm, based in part on our contributions, is that cells recognize viral infection as a disruption of cellular homeostasis. Thus, the long-term program vision is to use HSV as a tool to elucidate fundamental aspects of how cells recognize and respond to stress at the molecular level. In a recent screen, we uncovered a novel interaction between the immediate early HSV protein ICP0 and the cellular protein G3BP2. ICP0 is a multifunctional protein that enables virus replication in part by subverting host intrinsic and innate responses.  G3BP2 is an essential component of RNA stress granules (SGs), which form upon sensing of cellular stress and which have been associated with a variety of diseases. Recent studies indicate that many viruses either exploit or block SG formation, indicating that SGs play an important role in recognizing and mediating the outcome of a virus infection. Our preliminary studies suggest that ICP0 functions early during infection to block the formation of SGs, as efficient SGs formation is only visible following infection of HSV lacking ICP0 expression. The objectives of this proposal are to use our expertise in molecular virology, molecular biology and virus-host interactions to investigate the early events of HSV infection that trigger SG formation and to determine how SGs, and in particular G3BP2, modulate virus infection. We will also evaluate the importance of the interaction between ICP0 and G3BP2 on SG-dependent and SG-independent functions of G3BP2. Using resources, techniques and infrastructure that are well-established and available within my laboratory, these studies will enhance our understanding of basic cellular processes, such as induction of effective cell stress responses upon disruption of homeostasis. As these responses underlie the success of an organism as a whole, the generation of such fundamental knowledge will lead to a greater understanding of the basic mechamisms underlying many diseases.