Regulation of RIG-I-mediated anti-viral innate immunity by post-translational modifications

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Type I Interferons, namely Interferon alpha and Interferon beta, confer an anti-viral state to cells and limit virus replication and dissemination. To elicit an Interferon response mammalian hosts have evolved a variety of pattern recognition receptors, which sense components of invading pathogens and trigger downstream signaling cascades that lead to the transcriptional activation of Interferon alpha/beta. Among these are the Toll-like receptors and the recently identified cytosolic helicases RIG-I and MDA5. Unlike TLRs, RIG-I and MDA5 are ubiquitously expressed and play essential roles in the recognition of RNA viruses in various cell types. Tight regulation of immune signaling pathways is essential for a successful immune response against viral infections. RIG-I anti-viral activity is regulated by post-translational modifications. Lysine 63-linked ubiquitination of RIG-I by the E3 ubiquitin ligase TRIM25 is essential for the interaction of RIG-I with MAVS, a downstream signaling molecule of the pathway, and thereby for Interferon production. Moreover, further data suggest that phosphorylation of RIG-I might as well be important for RIG-I regulation. The proposed study is directed toward investigating the interplay between phosphorylation and ubiquitination to tightly regulate the RIG-I anti-viral interferon response. The main focus will lie on the characterization of the kinase(s) and phosphatase(s) involved in these processes. This study thus promises to identify novel key players of the cellular interferon response against viral infection.