TorsinA and Nuclear Envelope Function in HSV Infection

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DESCRIPTION (provided by applicant): Nuclear egress of herpesviruses is an essential and conserved process in virus replication. Over the past decade, viral proteins required for this process have been identified and functionally characterized. Progress in identification of cellular factors that participate in nuclear egress has been slower. Identification of cellular factors that participate in nuclear egress is highly significant from two points of view. On one hand, identification of essential factors might yield targets for antiviral therapy. On the other, characterization of the function of these factors will certainly provide insight into their normal functions in the uninfected cell. This is an important problem in human disease biology because many interesting inherited diseases are caused by mutations in genes that encode proteins of the nuclear envelope and its underlying lamina. These diseases include muscular dystrophies, cardiac, and bone and connective tissue disorders and torsion dystonias. In no case is the relationship between the mutant protein and disease pathogenesis completely clear. Here, we propose to explore the function of the torsinA gene product in HSV infection. Mutation of the gene encoding torsinA results in a neuromuscular disease called early-onset torsion dystonia, and the mechanism of disease is unclear. We have found preliminary evidence for a functional interaction between torsinA and herpes simplex type 1, and evidence specifically for a role for torsinA in regulation of membrane fusion at the nuclear envelope. We propose to fully characterize the interaction between torsinA and HSV pursuing two specific aims. Aim 1. Phenotypic characterization of the function of TorsinA in HSV-1 infection. We will use complementary approaches of TorsinA over-expression and knock-down/knock-out to test the hypothesis that normal Torsin expression is required for efficient HSV infection and to test the hypothesis that Torsin A is specifically required for efficient nuclear egress of HSV. Aim 2. Identification of the mechanism of TorsinA function in HSV infection. TorsinA function is thought to be mediated by interaction with, and regulation of, the activity of other proteins. Our preliminary data suggest that Torsin A might regulate HSV nuclear egress either by regulating the activity of previously identified cellular proteins or by directly regulating the function of HV glycoproteins in the nuclear envelope or the primary virion envelope. We will test both of these hypotheses using a combination of genetic and biochemical approaches.