Grant: Operating Grant

Herpesviruses are a large family of pathogens that infect and cause disease in diverse animals ranging from oysters to elephants. My laboratory studies the alphaherpesvirus subgroup that includes the human pathogens herpes simplex virus types 1 and 2 and varicella-zoster virus, the causative agent of chicken pox and shingles. Infections with these viruses are highly prevalent in Canadians, with upward of 30% of adults infected with herpes simplex virus type 1, for example. All viruses rely on components provided by host cells for the successful execution of their replication programs. It follows that there is a requirement for virus molecules to establish intimate relationships with cellular molecules. By identifying and understanding the mechanics of these critical virus-host cell interactions we hope to develop ways to disrupt these interactions and thereby create new methodologies for the treatment of herpes disease. We have demonstrated that the alphaherpesvirus structural protein Us2 binds to a cellular protein called ERK. Our experiments suggest that the interaction between Us2 and ERK promotes the release of infectious virus from cells. ERK is a very important cellular signaling molecule that participates in the regulation of cell growth, division and identity. It turns out that defects in the ERK signaling pathway are responsible for upwards of 30% of human cancers. Thus, there is a great deal of interest in understanding how ERK is regulated. We know that Us2 inhibits some ERK activities and stimulates others. What we don't yet understand is how Us2 interacts with ERK. Many cellular proteins have been identified that bind to ERK, but none of them look like Us2, so we think Us2 uses a novel mechanism for binding to ERK and regulating ERK activity. This grant application focuses on determining the molecular basis for the regulation of ERK activity by Us2 and how the ERK/Us2 interaction influences virus infection.