The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity

Abstract

AbstractType I interferons (IFN-Is) are essential for antiviral immunity but must be tightly regulated. The conserved transcriptional repressor SP140 inhibits interferon beta (Ifnb1) expression via an unknown mechanism. We find that SP140 does not repressIfnb1transcription but instead negatively regulatesIfnb1mRNA stability by directly repressing the expression of a previously uncharacterized regulator we call RESIST (REgulated Stimulator of Interferon via Stabilization of Transcript, previously annotated as Annexin-2 Receptor). RESIST promotesIfnb1mRNA stability by counteractingIfnb1mRNA destabilization mediated by the Tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within nuclear bodies, punctate structures that play important roles in silencing DNA virus gene expression in the nucleus. Consistent with this observation, we found that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 was independent of its ability to regulateIfnb1. Our results establish dual antiviral and interferon regulatory functions for SP140 and identify the SP140-RESIST pathway as a novel regulator ofIfnb1mRNA stability.