Symmetric Arginine Dimethylation Is Selectively Required for mRNA Splicing and the Initiation of Type I and Type III Interferon Signaling

Abstract

Summary: Alternative splicing is well understood to enhance proteome diversity as cells respond to stimuli. However, mechanistic understanding for how the spliceosome processes precursor messenger RNA (mRNA) transcripts to achieve template diversification is incomplete. We use recently developed enzymatic inhibitors of protein arginine methyltransferase 5 (PRMT5) and human naive T lymphocyte activation as a model system to uncover a precise set of mRNA transcripts that require symmetric arginine dimethylation. This methylation-dependent splicing selectivity is associated with a limited set of signaling pathways that are affected when PRMT5 is inhibited. Specifically, we identify a conserved role for symmetric arginine dimethylation in the induction of antiviral type I and type III interferon signaling following T cell receptor and pattern recognition receptor stimulation in human T lymphocytes and undifferentiated human THP-1 monocytes. Altogether, these findings reveal a mechanism by which cells may be enabled to precisely modulate transcript heterogeneity to orchestrate specific functional outcomes. : Metz et al. employ an optimized chemical toolkit to uncover the unexpected precision with which symmetric arginine dimethylation regulates mRNA splicing. They identify an associated requirement for PRMT5-dependent signaling in the production of antimicrobial type I and type III interferons that is conserved across innate and adaptive immune cells. Keywords: PRMT5, PRMT5 chemical toolkit, precursor mRNA splicing, type I and type III interferon signaling, human innate and adaptive immune system