The type I interferons (IFN) play a pivotal role in antiviral immune responses. As aberrant immune responses can be harmful to the host, innate immune signaling pathways are tightly regulated to minimize tissue damage. Aberrant activation of type I IFNs often leads to onset of inflammatory diseases including systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome (AGS) and vasculopathy. Despite a tremendous interest in uncovering the mechanisms underlying activation of the type I IFN signaling pathway, there is negligible understanding of mechanisms maintaining the resting state of this pathway. The endoplasmic reticulum (ER) is a major cellular organelle for protein synthesis and Ca2+ storage, that also acts as a signaling hub for the type I IFN responses. A major signaling adaptor for the type I IFN response, STING (stimulator of interferon genes, TMEM173) is located at the ER and, after sensing cytosolic DNA, translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi with the protein kinase TANK-binding kinase 1 (TBK1) to activate the transcription factor, interferon regulatory factor 3 (IRF3). The rate liming step for activation of the STING pathway is exit of STING from the ER. It was suggested that ?ER retention factors? should exist to prevent aberrant activation of STING, but the molecular identity of these factors is currently not known. This study stems from identification of STIM1 as an interacting partner of STING. Accordingly, in this proposal we will uncover the molecular mechanisms involved in STIM1-mediated regulation of the STING pathway as well as physiological role of STIM1 in activation of the STING pathway after induction of autoimmunity. A mechanistic understanding of how the inactive state of type I IFN response is maintained can have therapeutic potential to alleviate chronic inflammatory diseases, and in a long term, enhance vaccination efficacy and checkpoint blockade-based cancer therapy.
STATEMENT This study will uncover novel mechanisms involved in regulation of the type I interferon signaling pathways. It is significant because it will not only advance basic science research but also provide novel therapeutic targets to treat autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus, which are highly prevalent in the United States (>20% of the population).
