Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-κB activity in invaded epithelial cells

PLoS Pathog. 2013;9(6):e1003409. doi: 10.1371/journal.ppat.1003409. Epub 2013 Jun 6.


NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Bacterial Secretion Systems / genetics
  • COS Cells
  • Chlorocebus aethiops
  • Dysentery, Bacillary / enzymology*
  • Dysentery, Bacillary / genetics
  • Dysentery, Bacillary / pathology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / microbiology
  • Epithelial Cells / pathology
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Proteolysis*
  • Shigella / enzymology*
  • Shigella / genetics
  • Signal Transduction / genetics
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics


  • Bacterial Proteins
  • Bacterial Secretion Systems
  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • Ubiquitin-Protein Ligases
  • Protein Kinase C
  • Proteasome Endopeptidase Complex

Grant support

This work was supported by Grant-in-Aid for Specially Promoted Research (23000012 (CS)); a Grant-in-Aid for Young Scientists (B) (23790472 (HA)) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Part of this work was supported by grants from the Naito Foundation (HA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.