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Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst

Author

Listed:
  • Daniel B. Graham

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital, Harvard Medical School)

  • 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
    Massachusetts General Hospital, Harvard Medical School
    Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School)

  • Dan Knights

    (University of Minnesota)

  • Amanda Mok

    (Broad Institute of MIT and Harvard)

  • Aylwin C.Y. Ng

    (Broad Institute of MIT and Harvard
    Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School)

  • 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
    Massachusetts General Hospital, Harvard Medical School
    Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
    Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School)

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.

Suggested Citation

  • 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 & Ramnik J. Xavi, 2015. "Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8838
    DOI: 10.1038/ncomms8838
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    Cited by:

    1. Meiyue Wang & Heinrich Flaswinkel & Abhinav Joshi & Matteo Napoli & Sergi Masgrau-Alsina & Julia M. Kamper & Antonia Henne & Alexander Heinz & Marleen Berouti & Niklas A. Schmacke & Karsten Hiller & E, 2024. "Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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