PYK2 controls intestinal inflammation via activation of IRF5 in macrophages

Abstract

17Inflammatory bowel disease (IBD) is a group of inflammatory disorders of the gastro-intestinal 18 tract caused by a complex combination of genetic and environmental factors. Interferon 19 regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, which plays a 20 key pathogenic role in mouse colitis models and is a genetic risk factor for IBD. A screen of a 21 protein kinase inhibitor library in macrophages revealed a list of putative IRF5 kinases. Among 22 MAIN 36A recent single-cell transcriptomic analysis of colon biopsies from patients with ulcerative 37 colitis (UC) provided a framework for linking GWAS risk loci with specific cell types and 38 functional pathways and helped to nominate causal genes across GWAS loci 3 , amongst them 39Interferon regulatory factor 5 (IRF5). IRF5 is a multifunctional regulator of immune 40 responses 4-6 . The IRF5 risk variant has consistent effects across monocytes and macrophage 41 conditions, but also impacts gene expression and splicing across a wide range of other immune 42 cells and tissues 7 . 43Recent studies using IRF5-deficient mice have established a critical role of this transcription 44 factor in the pathogenesis of mouse models of colitis 8,9 . IRF5 is proposed to exert its molecular 45 function via a cascade of events involving its phosphorylation, ubiquitination, dimerisation, 46 nuclear translocation and selective binding to its target genes to enable their expression 10 . 47 PYK2-deficient cells (Fig. 2f, Supplementary Fig. 4a, b). Interestingly, we could only detect 130 Y171 phosphorylation in WT cells (Fig. 2f, g Supplementary Fig. 4b), while S56 and Y312 131 residues were modified in PYK2-deficient cells (Fig. 2f, Supplementary Fig. 4a, b), possibly 132 reflecting on modification by other enzymes. In fact, Src tyrosine kinase Lyn was capable of 133 phosphorylating IRF5 at orthologues of Y312 and Y334 sites in in vitro co-expression 134 system 19 . We individually mutated these sites (Y171, Y312, Y334) as well as the published 135

Genetic insights into the association between inflammatory bowel disease and Alzheimer’s disease

“…PTK2B encodes a cytoplasmic protein tyrosine kinase which is involved in calcium-induced regulation of ion channels and activation of the map kinase signaling pathway. It has been identified as a key regulator of interferon regulating factor 5 activation, macrophage inflammatory response, and intestinal pathology (34), and it is wellknown to be associated with risk of late onset AD (32). BNIP3L was reported to mitigate mitochondrial damage during intestinal inflammation, which is very important during IBD pathogenesis (37), it was also found reduced in AD patient samples (38).…”

“…PTK2B has been reported to play a role in monocyte migration (30) and neutrophil degranulation (31), and it is well-known to be associated with risk of late onset AD (32) and to have an eQTL in monocytes (33). Moreover, Pyk2 has been identified as a key regulator of Interferon regulating factor 5 activation (an important IBD susceptibility gene), macrophage inflammatory response, and intestinal pathology (34).…”