Mechanism of SUMOylation-Mediated Regulation of Type I IFN Expression

Type I interferons (IFN) are cytokines that bridge the innate and adaptive immune response, and thus play central roles in human health, including vaccine efficacy, immune response to cancer and pathogen infection, and autoimmune disorders. Post-translational protein modifications by the small ubiquitin-like modifiers (SUMO) have recently emerged as an important regulator of type I IFN expression as shown by studies using murine and cellular models and recent human clinical trials. However, the mechanism regarding how SUMOylation regulates type I IFN expression remains poorly understood. In this study, we show that SUMOylation inhibition does not activate IFNB1 gene promoter that is regulated by known canonical pathways including cytosolic DNA. Instead, we identified a binding site for the chromatin modification enzyme, the SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1), located between the IFNB1 promoter and a previously identified enhancer. We found that SETDB1 regulates IFNB1 expression and SUMOylation of SETDB1 is required for its binding and enhancing the H3K9me3 heterochromatin signal in this region. Heterochromatin, a tightly packed form of DNA, has been documented to suppress gene expression through suppressing enhancer function. Taken together, our study identified a novel mechanism of regulation of type I IFN expression, at least in part, through SUMOylation of a chromatin modification enzyme.