The activities of many viral proteins required for viral DNA replication and morphogenesis are regulated by phosphorylation. That this is the case in vaccinia virus (VV), which is the best-understood member of the Poxviridae, is increasingly clear. Poxviruses encode the vast majority of their own enzymatic components required for the transcription and replication of their viral genome. This remarkable autonomy from the host makes VV one of the most premier eukaryotic biochemical and genetic model systems available. The study of VV continues to shed light on parallel systems such as DNA replication, chromatin condensation, post-translational modification of proteins, and dynamic aspects of kinases and phosphatases. In particular, VV encodes two protein kinases (F10 and B1) and a dual-specificity phosphatase (H1). These enzymes are all essential in the viral life cycle. However, the precise molecular role dynamic phosphorylation plays during the viral life cycle remains largely undefined. The vaccinia viral protein that is at the heart of this research, Vp11, is an 11-kDa-phosphoserine protein. Although Vp11 (encoded by the gene F17) is the most abundant protein (in terms of number of molecules) in the virion, its precise in vivo function(s) remains elusive. As such, the primary goal of this research is to determine the in vivo function(s) of Vp11. Vp11 binds to DNA in vitro, and has long been postulated to be involved in condensation of the viral genomic DNA. By modulating nucleic acid-binding activity, protein phosphorylation can be a positive or negative regulator of gene expression. Phosphorylation may also be necessary for the oligomerization of a protein. Furthermore, protein phosphorylation can also be required for the proper subcellular localization of a protein, or may be critical for the protein's stability in vivo. This project is designed to explore these scenarios. Recent results from this project point to an important role of the MAP/ERK kinase-signaling pathway during the VV life cycle. The proven tractability of vaccinia as a model system allows a dissection of this possible contribution of the host cell. Aspects of these processes are addressed within this project by a focused molecular characterization of Vp11 as well as the role of the MAP/ERK signaling pathway in the life cycle of poxviruses.

The research described in this project involves an animal virus called vaccinia. Vaccinia was the live vaccine used to eradicate smallpox. The study of vaccinia virus by biochemists has long provided insights into the more complicated workings of human cells. For the correct growth of a human cell, many forms of control (also called "regulation") are required. Without this regulation, cell growth becomes abnormal. The most common type of regulation is a simple chemical process by which a phosphate ion is placed on certain types of protein. Regulation of this sort is termed "phosphorylation". This NSF-funded research will provide a window into this crucial event by using a much simpler, and therefore more tractable, viral model system.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Jo Ann Wise
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University of Wisconsin Milwaukee
United States
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