Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1

J Cell Biochem. 2013 Oct;114(10):2284-92. doi: 10.1002/jcb.24573.

Abstract

The Helicobacter pylori virulence factor CagA targets a variety of host proteins to alter different cellular responses, including the induction of pro-inflammatory cytokines. We have previously shown that CagA-facilitated lysine 63-linked ubiquitination of TAK1 is essential for the H. pylori-induced NF-κB activation and the expression of proinflammatory cytokines. However, the molecular mechanism for TAK1 ubiquitination and activation in H. pylori-mediated NF-κB activation remains elusive. Here, we identify lysine 158 of TAK1 as the key residue undergoing lysine 63-linked ubiquitination in response to H. pylori infection. Mutation of lysine 158 to arginine prevents the ubiquitination of TAK1 and impairs H. pylori-induced TAK1 and NF-κB activation. Moreover, we demonstrate that E2 ubiquitin conjugating enzyme Ubc13 is involved in H. pylori-mediated TAK1 ubiquitination. Suppressing the activity of Ubc13 by a dominant-negative mutant or siRNA abolishes CagA-facilitated and H. pylori-induced TAK1 and NF-κB activation. These findings further underscore the importance of lysine 63-linked ubiquitination of TAK1 in H. pylori-induced NF-κB activation and NF-κB-mediated inflammatory response.

Keywords: CagA; NF-κB; TAK1; UBIQUITINATION; Ubc13.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Helicobacter pylori / pathogenicity*
  • Host-Pathogen Interactions
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lysine / metabolism*
  • MAP Kinase Kinase Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitination / genetics
  • Ubiquitination / physiology*

Substances

  • NF-kappa B
  • UBE2N protein, human
  • Ubiquitin-Conjugating Enzymes
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Lysine