The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses

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PROJECT SUMMARY/ABSTRACT Infections with oncogenic, DNA viruses account for twelve percent of human cancers and are a major cause of mortality and morbidity throughout the world. The development of new therapeutics to treat viral infections would significantly benefit from a detailed understanding of the host response to this infectious insult. The ability of the immune system to counteract viral infection is often mediated through a sophisticated repertoire of proteins that bind to viral nucleic acids. In response to DNA derived from viruses, the host protein cyclic GMP- AMP (cGAMP) Synthase (cGAS) produces the signaling nucleotide cGAMP, which initiates host inflammation to clear infection by binding to the protein Stimulatory of Interferon Genes (STING). However, second messenger signal transduction systems often rely on a variety of protein receptors to drive cellular responses. Whether cGAMP can function beyond STING activation to restrict viral infection and oncogenesis remains largely unknown. Recent studies have shown that cGAS and STING can have non-overlapping effects on infection outcome, suggesting that cGAS plays multiple roles in response to viral infection beyond signaling through STING. To systematically address this hypothesis, we have generated beads coated in cGAMP that are able to isolate cGAMP-binding proteins from cell extracts. Using this method, we have identified two new proteins other than STING that can bind to cGAMP. These novel cGAMP binding proteins have known roles in regulating cellular processes involved in the host response to infection including how the cell produces energy as well as biosynthetic building blocks, fundamental aspects of cellular physiology that viruses rely upon in order to facilitate replication. Here, I propose to utilize structure-function analysis coupled with biochemical and infection models to interrogate the biological relevance of these previously unrecognized cGAMP-binding proteins and detail their effects on viral restriction. The findings from these studies will significantly inform the mechanisms by which the host immune system can restrict viral infection and oncogenesis and may provide new therapeutic strategies to combat infectious and malignant diseases.