The antiviral nuclear body protein SP140 represses Ifnb1 transcript stabilization by the novel regulator RESIST [ATAC-seq]

Negative regulation of the antiviral cytokine IFN-I is critical to prevent host pathology, but is not fully understood. The highly conserved but understudied epigenetic reader and nuclear body protein SP140 represses IFN-I by an unknown mechanism. We describe the mechanism by which SP140 negatively regulates IFN-I, and include ATAC-seq data of WT (B6) and SP140 KO BMMs untreated or treated with 100 ug/mL DMXAA for 8 hours in this dataset. We found that SP140 represses the expression of a novel positive regulator of IFN-I previously annotated as an annexin II receptor, which we rename RESIST (REgulated Stimulator of IFN-I via Stabilization of Transcript). RESIST promotes IFN-I mRNA stability by binding the CCR4-NOT mRNA deadenylase complex and blocking recruitment of the TTP family of RNA-binding proteins, which negatively regulate IFN-I mRNA stability, to CCR4-NOT. Mechanistically, RESIST uses N and C-terminal alpha-helices respectively to either dock to the CCR4-NOT complex or block TTP family binding. Our work reveals a new regulator of IFN-I and a new mechanism regulating IFN-I mRNA stability.