Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst

Daniel B. Graham (), Christine E. Becker, Aivi Doan, Gautam Goel, Eduardo J. Villablanca, Dan Knights, Amanda Mok, Aylwin C.Y. Ng, John G. Doench, David E. Root, Clary B. Clish and Ramnik J. Xavier ()
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Daniel B. Graham: Broad Institute of MIT and Harvard
Christine E. Becker: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Aivi Doan: Broad Institute of MIT and Harvard
Gautam Goel: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Eduardo J. Villablanca: Broad Institute of MIT and Harvard
Dan Knights: University of Minnesota
Amanda Mok: Broad Institute of MIT and Harvard
Aylwin C.Y. Ng: Broad Institute of MIT and Harvard
John G. Doench: Broad Institute of MIT and Harvard
David E. Root: Broad Institute of MIT and Harvard
Clary B. Clish: Broad Institute of MIT and Harvard
Ramnik J. Xavier: Broad Institute of MIT and Harvard

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8838

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