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

Amrita Kumar, Huixia Wu, Lauren S Collier‐Hyams, Jason M Hansen, Tengguo Li, Kosj Yamoah, Zhen‐Qiang Pan, Dean P Jones, Andrew S Neish

Author Affiliations

  1. Amrita Kumar1,,
  2. Huixia Wu1,,
  3. Lauren S Collier‐Hyams1,
  4. Jason M Hansen2,
  5. Tengguo Li3,
  6. Kosj Yamoah4,
  7. Zhen‐Qiang Pan4,
  8. Dean P Jones5 and
  9. Andrew S Neish*,1
  1. 1 Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
  2. 2 Division of Pulmonary, Asthma, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University, Atlanta, GA, USA
  3. 3 Department of Biology, Emory University, Atlanta, GA, USA
  4. 4 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA
  5. 5 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA, USA
  1. *Corresponding author. Epithelial Pathobiology Unit, Department of Pathology, Emory University School of Medicine, Room 105‐F, Whitehead Bldg, 615 Michael Street, Atlanta, GA 30322, USA. Tel.: +1 404 727 8545; Fax: +1 404 727 8538; E-mail: aneish{at}emory.edu
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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.

  • Received May 11, 2007.
  • Accepted September 5, 2007.
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