Differential expression and signaling domains of IL- 17RC
Ho, Allen Wayne
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An effective immune response requires the functional coordination of a number of different cellular mediators. Cytokines represent soluble molecules that allow for the spatial and temporal intersection of multiple immune networks. The interleukin-17 (IL-17) cytokine family members IL-17A and IL-17F mediate inflammatory activities via the IL-17 receptor (IL-17R) complex, comprised of the IL-17RA and IL-17RC subunits. Proper regulation of the IL-17 signaling axis results in effective host defense against extracellular pathogens, while aberrant signaling can drive autoimmune pathology. Elucidating the molecular mechanisms underlying IL-17 signal transduction can yield an enhanced understanding of inflammatory immune processes and also create an avenue for therapeutic intervention in the treatment of IL-17-dependent diseases. To date, the fundamental signaling mechanisms used by the IL-17R complex are still incompletely defined. While current structure-function studies have primarily focused on the IL-17RA subunit, recent research indicates that the IL-17RC subunit plays a key role in modulating IL-17 responses. Therefore, this thesis aims to address the molecular and cellular functions of IL-17RC. Specifically, work presented herein demonstrates that the ST-2 murine fibroblast cell line may encode soluble IL-17RC splice variants that may bind novel ligands. Moreover, IL-17RC is required for driving host defense against Candida albicans infection in the oral cavity, establishing its absolute requirement for IL-17-dependent signaling. To biochemically mediate downstream signaling, IL-17RC associates with a glycosylated IL-17RA isoform upon ligand-binding and recruits a phosphorylated Act1 isoform via a key signaling domain on the IL-17RC cytoplasmic tail. Furthermore, IL-17RC interacts with novel signaling intermediates to mediate IL-17 signal transduction. Overall, this thesis describes research that establishes a model for signaling downstream of IL-17RC and provides a framework for future work on this important subunit and its impact on human health.