The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Type 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 repress Ifnb1 transcription but instead negatively regulates Ifnb1 mRNA 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 promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA 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 regulate Ifnb1 . Our results establish dual antiviral and interferon regulatory functions for SP140 and identify the SP140-RESIST pathway as a novel regulator of Ifnb1 mRNA stability.
