Cellular Homologs Of Herpesvirus Genes

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Abstract

Viruses have developed strategies to counteract host defenses so as to allow viruses to infect cells and result in a latent or persistent infection. The goal of this project is to identify and determine the function of viral proteins that interact with host cell proteins to influence the course of infection. These proteins may allow us to identify new molecules that are important in the human immune system. Programmed cell death (apoptosis) is an antiviral defense mechanism used by the host to eliminate virus-infected cells. Some viruses, which cause chronic infections, encode proteins that inhibit cell death which may allow the infected cells with the viruses to avoid destruction by the host's immune system. We have studied the mechanism by which a protein encoded by a human poxvirus, molluscum contagiosum virus, prevents cell death. Molluscum contagiosum virus is a frequent cause of skin lesions in children and can cause disfiguring lesions in immunosuppressed patients. We found that the molluscum contagiosum virus 159 protein (MC159) can inhibit cell death and we identified regions of the protein that are important for its activity. The MC159 protein contains two death effector domains (DEDs) that inhibit apoptosis. We found that the parts of the protein before the first DED and after the second DED were dispensable for its ability to block apoptosis. By making mutations in the protein, we showed that both DEDs, in their correct order, are needed to prevent apoptosis. Previously, we showed that the DEDs of MC159 bind to cellular proteins termed caspase-8 and FADD. While some of the MC159 mutants bound to FADD and/or caspase-8, they could not block apoptosis. Thus, binding of the DEDs of MC159 to FADD and caspase-8 is not sufficient for the ability of MC159 to block apoptosis.