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Author Notes:

Author correspondence: Andrew S Neish, Epithelial Pathobiology Unit, Department of Pathology, Emory University School of Medicine, Room 105-F, Whitehead Bldg, 615 Michael Street, Atlanta, GA 30322, USA. Telephone: 404-727-8545. Fax: 404-727-8538. Email: aneish@emory.edu.

Amrita Kumar and Huixia Wu share primary authorship.

We thank J David Lambeth and Keith D Wilkinson for helpful discussions.

Subjects:

Research Funding:

This work was supported in part by National Institutes of Health grants DK-071604 and AI-064462 to ASN, DK-68105 to LSC-H, and DK-064399.

Keywords:

  • commensal
  • NEDD8
  • NF-κB
  • reactive oxygen species
  • Ubc12

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

Tools:

Journal Title:

EMBO Journal

Volume:

Volume 26, Number 21

Publisher:

, Pages 4457-4466

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 β-catenin and the NF-κB inhibitor IκB-α. Ubiquitination of these proteins as well as others is catalyzed by the SCFβTrCP 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-κB and β-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.

Copyright information:

© 2007 European Molecular Biology Organization

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