Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Genomics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • NADPH Oxidase 2
  • NADPH Oxidases / metabolism*
  • Phagocytes / metabolism*
  • Phosphofructokinase-1 / metabolism
  • Respiratory Burst*
  • Staphylococcus aureus


  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Membrane Glycoproteins
  • Membrane Proteins
  • RNF145 protein, mouse
  • Rbpj protein, mouse
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Phosphofructokinase-1