RBM39 shapes innate immunity through transcriptional and splicing control of IRF3 and other key factors

Abstract

AbstractRNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses, affecting transcription and/or splicing of key pathway components, in particular interferon regulatory factor 3 (IRF3). Knockdown ofRBM39or treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA), lipopolysaccharide (LPS) and viral infections mediated by IRF3.RBM39knockdown further restrained the type III interferon (IFN) pathway, by reducing expression of the receptor subunit Interleukin 10 Receptor Subunit Beta (IL-10RB). RNAseq and mass spectrometry revealed altered expression of additional signaling factors, highlighting the importance of RBM39 in orchestrating innate immunity.One Sentence SummaryRBM39 acts as a novel innate immune factor by regulating transcription and/or alternative splicing of IRF3 and several other key proteins involved in innate immune responses.