Serine Arginine Splicing Factor 7 (SRSF7) is a critical regulator of innate immune activation in macrophages

Abstract

Abstract Macrophages are immune cells that receive signals from pathogens and respond by reprogramming gene expression to activate an innate immune response. We currently have a poor understanding of how this response is fine-tuned at a post-transcriptional level. To address this, we turned to recent proteomics studies that identified mRNA processing as a pathway enriched for differentially phosphorylated proteins in macrophages infected with the important human pathogen Mycobacterium tuberculosis (Mtb). We became interested in one of these mRNA processing proteins, a splicing regulatory factor called SRSF7 (formerly known as 9G8), that was differentially phosphorylated at three serine residues during early Mtb infection. Transcriptomics analysis of SRSF7 knockdown RAW 264.7 macrophage-like cells revealed that SRSF7 is required for proper expression of a group of innate immune transcripts including the antiviral genes Mx1 and Ifit3 and the cytosolic DNA sensor Zbp1. Consistent with this phenotype, SRSF7 KD macrophages are permissive to Vesicular Stomatitis Virus (VSV) hyper replication. On the other hand, overexpression of SRSF7 in RAW 264.7 cells leads to elevated ISG abundance in resting cells and enhanced ability to restrict VSV replication. Curiously, it appears that certain ISGs are more reliant on SRSF7 than others, suggesting that SRSF7 acts at the level of the RNA itself. We have started to implicate phosphorylation of SRSF7 in these phenotypes. Together, these studies provide some of the best evidence to date that pathogen sensing cascades can functionalize RNA binding proteins during macrophage activation and highlight a previously unappreciated role for SRSF7 in controlling macrophage antiviral responses. Supported by grants from 1F31GM143893-01 NIH Predoctoral Fellowship and R35GM133720 from NIH/NIGMS.