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

RNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism and development. A genome-wide CRISPR/Cas9 screen in two liver-derived cell lines 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 of RBM39 or 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. RBM39 knockdown further restrained the type III interferon (IFN) pathway, by reducing expression of the receptor subunit Interleukin 10 Receptor Subunit Beta (IL-10RB). RNAseq experiments in PH5CH cells where RBM39 was knocked down or Indisulam treatment was performed revealed altered expression of additional signaling factors, highlighting the importance of RBM39 in orchestrating innate immunity.