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Nat Commun DOI:10.1038/ncomms8838

Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.

Publication TypeJournal Article
Year of Publication2015
AuthorsGraham, DB, Becker, CE, Doan, A, Goel, G, Villablanca, EJ, Knights, D, Mok, A, C Y Ng, A, Doench, JG, Root, DE, Clish, CB, Xavier, RJ
JournalNat Commun
Volume6
Pages7838
Date Published2015 Jul 21
ISSN2041-1723
KeywordsAnimals, Base Sequence, Cell Line, Genomics, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Membrane Glycoproteins, Membrane Proteins, Mice, Molecular Sequence Data, NADPH Oxidase, Phagocytes, Phosphofructokinase-1, Respiratory Burst, Staphylococcus aureus
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.

URLhttp://dx.doi.org/10.1038/ncomms8838
DOI10.1038/ncomms8838
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26194095?dopt=Abstract

Alternate JournalNat Commun
PubMed ID26194095
PubMed Central IDPMC4518307
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States