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Nat Commun. 2015 Jul 21;6:7838. doi: 10.1038/ncomms8838.

Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.

Author information

1
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
2
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
3
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
4
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
5
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
6
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
7
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [4] Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [5] Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

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.

PMID:
26194095
PMCID:
PMC4518307
DOI:
10.1038/ncomms8838
[Indexed for MEDLINE]
Free PMC Article

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