Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Graham, 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 |
Journal | Nat Commun |
Volume | 6 |
Pages | 7838 |
Date Published | 2015 Jul 21 |
ISSN | 2041-1723 |
Keywords | Animals, 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. |
URL | http://dx.doi.org/10.1038/ncomms8838 |
DOI | 10.1038/ncomms8838 |
Pubmed | |
Alternate Journal | Nat Commun |
PubMed ID | 26194095 |
PubMed Central ID | PMC4518307 |
Grant List | P30 DK043351 / DK / NIDDK NIH HHS / United States U01 DK062432 / DK / NIDDK NIH HHS / United States DK043351 / DK / NIDDK NIH HHS / United States |
Nat Commun DOI:10.1038/ncomms8838
Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst.
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