Chicken IRF10 suppresses the cGAS-STING-IFN antiviral signaling pathway by targeting IRF7

Introduction: The innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-interferon (IFN) signaling axis is a cornerstone of antiviral innate immunity in chickens, with chicken interferon regulatory factor 7 (chIRF7) serving as the principal transcription factor downstream chSTING to initiate type I IFN production. Although the chicken interferon regulatory factor (IRF) family consists of eight members, the roles of those beyond chIRF7 in this pathway remain largely unexplored. Methods: Systematic screening was performed to analyze the roles of chicken IRF family members in the cGAS-STING-IFN antiviral signaling. Combined molecular biological and biochemical methods were utilized to explore the action mechanism of chIRF10 as a negative regulator of cGAS-STING-IFN antiviral signaling pathway in transfected cells and gene knockout cells, with or without different virus infections. Results: The chIRF10 was identified as a potent negative regulator of chicken cGAS-STING-IFN antiviral signaling. Mechanistically, chIRF10 mediated suppression required its IRF associated domain (IAD) but not its DNA binding domain (DBD). chIRF10 inhibited IFN activation triggered by cGAS-STING, as well as by the downstream kinases TBK1/IKKε and the transcription factor IRF7. Importantly, chIRF10 physically interacted with chIRF7 via its IAD, impairing chIRF7 dimerization and activation. Discussion: Collectively, these findings unveil a novel immunoregulatory function of chIRF10 and delineate a previously unrecognized mechanism fine-tuning the chicken cGAS-STING-IFN antiviral pathway, offering potential insights for developing interventions against avian viral diseases.