An effective innate immune response is essential for survival of pathogenic infections. Interferons? are critical cytokine mediators of cellular defense, and they are produced in response to viral infections? and act on neighboring cells to confer resistance to infection. Interferons bind to cell surface receptors? and stimulate a signal transduction pathway to the nucleus that induces the transcription of a subset of? genes. The products of the newly induced genes act coordinately to establish an effective host? defense. Although a few genes have been identified that exhibit antiviral activity, these are not? sufficient to account for the antiviral effects of interferon. The infected cell produces many proteins in? addition to interferon, and these proteins may also function to curb dissemination of the virus. The? roles of many genes induced in the infected cell remain to be determined. One gene that is induced in? response to viral infection and to interferon is called interferon stimulated gene factor 54 (ISG54).? ISG54 appears to be a member of a family of proteins that possess tetratricopeptide repeats.? However, little else is known of the function of ISG54. Our preliminary data suggest that ISG54? decreases cell viability, and in this way it may contribute to reduction of viral dissemination. The broad? goal for this exploratory/developmental research proposal is to initiate studies that will elucidate the? mechanism by which ISG54 expression contributes to innate immunity.? Our approaches will include analyses to 1) Determine the cellular localization of ISG54, 2)? Establish the effect of ISG54 on cell viability, 3) Identify interacting partners of ISG54, and 4) Evaluate? the role of ISG54 in viral defense. The transcriptional induction of ISG54 in response to virus,? interferon, DNA damage, and Toll-receptor signaling indicates that it plays a critical role in the cellular? defense response. Knowledge of the function of ISG54 may provide a new avenue to intervene and? treat infections.?
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