Abstract
The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency.
Highlights
The phagocyte oxidative burst, mediated by Nox[2] NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens
Genome-wide association studies (GWAS) have implicated genetic loci associated with risk for inflammatory bowel disease (IBD) and allowed for inference of new biological processes that contribute to disease[14]
We addressed the possibility that these three regulatory nodes function in a cell type-dependent manner by performing the same experiment in bone marrowderived dendritic cells (BMDCs)
Summary
The phagocyte oxidative burst, mediated by Nox[2] NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Among pathways that positively regulate oxidative burst, adhesion-dependent signalling through immunoreceptor tyrosine-based activation motifs (ITAMs) profoundly augments Nox[2] NADPH oxidase activity in response to inflammatory mediators[9] In this context, Src and Syk kinases direct the assembly of a signalling complex comprised of Slp[76], Vav and PLC-g2, which elicits calcium flux and production of diacylglycerol. Human genetics offers an opportunity to leverage insight from large amounts of genetic variation within healthy and patient populations to interrogate mechanisms of immunity Irrespective of their putative roles in IBD pathology, genes within risk loci are likely to be highly enriched for genes controlling immune signalling pathways. We further define the mechanistic basis of transcriptional, metabolic and ubiquitin-dependent regulation of the oxidative burst
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