Tuesday, October 15, 2024
10/15/2024
PROJECT SUMMARY / ABSTRACT Well controlled antiviral innate immunity is essential for restricting viral pathogens while preventing aberrant inflammation. A key antiviral signaling pathway is initiated by RIG-I-like receptors (RLRs) which sense viral RNA in the cytosol to induce the production of interferons through a higher order signaling platform centered on the adaptor protein MAVS. Although the components of the MAVS signalosome are basally expressed, RLR signaling only proceeds when they coalesce around MAVS at ER-mitochondrial contact sites. Many of the protein-protein interactions and post-translational modifications required for the proper function of the MAVS signalosome are known. While, functional interactions in protein complexes can be mediated by RNA molecules, whether RNA molecules play a role in signaling through the MAVS signalosome remains unexplored. I have found that 1) MAVS is associated with non-viral RNA, that 2) RNA promotes signaling through the MAVS signalosome, and that 3) canonical RNA-binding proteins (RBPs) interact with MAVS. This proposal aims to define the functional roles for RNA and RBPs in regulating antiviral signaling through the MAVS signalosome. During the mentored phase, I will gain new training in the characterization of RNA-protein interactions through biochemical, sequencing-based, and quantitative proteomic approaches, as well as the virological techniques required to study RNA viruses and innate immunity. In Aim 1, I will define the RNA-dependent interactions between components of the MAVS signalosome during the K99 phase, and identify novel proteins that associate with RNA during RLR signaling at the R00 phase. Through Aim 2, I will pinpoint the sequences in MAVS required for RNA-association, and identify a high-confidence set of MAVS-bound RNAs during the K99 phase. During the R00 stage, I will functionally dissect the roles for these RNAs at the MAVS signalosome. In Aim 3, I will screen a shortlist of MAVS-associated RBPs to identify those that influence MAVS signaling during the K99 stage, and determine the molecular functions of three RBPs (STAU1, HNRNPL, and RBM10) in antiviral signaling at the R00 stage. The overall outcome of these experiments will be to define new RNA-centric principles by which the MAVS signalosome is organized. Understanding how RNA molecules influence antiviral signaling could unlock new host-directed therapeutic strategies against viral diseases as well as autoimmune disorders. In addition to my advisor Dr. Savan, I have assembled an Advisory Committee with expertise in the different facets of my research. Together, this excellent training environment at the University of Washington will augment my research during the mentored phase, and equip me with the skills required to transition to an independent academic researcher studying the RNA regulation of innate immune processes.
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