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Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species.

The EMBO journal | Oct 31, 2007

The resident prokaryotic microflora of the mammalian intestine influences diverse homeostatic functions of the gut, including regulation of cellular growth and immune responses; however, it is unknown how commensal prokaryotic organisms mechanistically influence eukaryotic signaling networks. We have shown that bacterial coculture with intestinal epithelial cells modulates ubiquitin-mediated degradation of important signaling intermediates, including beta-catenin and the NF-kappaB inhibitor IkappaB-alpha. Ubiquitination of these proteins as well as others is catalyzed by the SCF(betaTrCP) ubiquitin ligase, which itself requires regulated modification of the cullin-1 subunit by the ubiquitin-like protein NEDD8. Here we show that epithelia contacted by enteric commensal bacteria in vitro and in vivo rapidly generate reactive oxygen species (ROS). Bacterially induced ROS causes oxidative inactivation of the catalytic cysteine residue of Ubc12, the NEDD8-conjugating enzyme, resulting in complete but transient loss of cullin-1 neddylation and consequent effects on NF-kappaB and beta-catenin signaling. Our results demonstrate that commensal bacteria directly modulate a critical control point of the ubiquitin-proteasome system, and suggest how enteric commensal bacterial flora influences the regulatory pathways of the mammalian intestinal epithelia.

Pubmed ID: 17914462 RIS Download

Mesh terms: Animals | Bacteroides | Cell Cycle Proteins | Cullin Proteins | Epithelial Cells | Escherichia coli | Humans | I-kappa B Proteins | Intestines | Lactobacillus rhamnosus | NF-KappaB Inhibitor alpha | NF-kappa B | Oxidative Stress | Rats | Reactive Oxygen Species | Signal Transduction | Ubiquitin | Ubiquitins | beta Catenin

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Associated grants

  • Agency: NIAID NIH HHS, Id: R56 AI064462
  • Agency: NIDDK NIH HHS, Id: DK-68105
  • Agency: NIDDK NIH HHS, Id: DK-071604
  • Agency: NIDDK NIH HHS, Id: K01 DK068105
  • Agency: NIDDK NIH HHS, Id: R24 DK064399
  • Agency: NIDDK NIH HHS, Id: R01 DK071604
  • Agency: NIAID NIH HHS, Id: AI-064462
  • Agency: NIDDK NIH HHS, Id: DK-064399
  • Agency: NIAID NIH HHS, Id: R01 AI064462

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