CK1α suppresses autoimmunity by restraining the cGAS-STING signaling

Stimulator of interferon genes (STING), the central hub protein of the cGAS-STING signaling, is essential for type I IFN production of innate immunity. However, prolonged or excessive activation of STING is highly related to autoimmune diseases, most of which exhibit the hallmark of elevated expression of type I interferons and IFN-stimulated genes (ISGs). Thus, the activity of STING must be stringently controlled to maintain immune homeostasis. Here, we reported that CK1α, a protein serine/threonine kinase, was essential to prevent the over-activation of STING-mediated type I IFN signaling through autophagic degradation of STING. Mechanistically, CK1α interacted with STING upon the cGAS-STING pathway activation and promoted STING autophagic degradation by enhancing the phosphorylation of p62 at serine 349, which was critical for p62 mediated STING autophagic degradation. Consistently, SSTC3, a selective CK1α agonist, significantly attenuated the response of the cGAS-STING signaling by promoting STING autophagic degradation. Importantly, pharmaceutical activation of CK1α using SSTC3 markedly repressed the systemic autoinflammatory responses in the Trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CK1α in the autophagic degradation of STING to maintain immune homeostasis. Manipulating CK1α through SSTC3 might be a potential therapeutic strategy for alleviating STING-mediated aberrant type I IFNs in autoimmune diseases. Total RNA was isolated and sequenced by deep sequencing using Illumina HiSeq 2500