New insights into a complex host-pathogen interaction: mechanisms of Helicobacter pylori activation of NF-κB

Helicobacter pylori infection is the main cause of chronic gastritis, gastric ulcers and gastric cancer. The gram-negative spirochete, which infects more than half of the world’s population, is recognized by the International Agency for Research on Cancer as a group 1 carcinogen. The mechanism by which H. pylori induces carcinogenesis is believed to be its ability to cause chronic inflammation, creating an environment suitable to tumor initiation and progression. Many different strains of H. pylori exist, but those strains harboring the cag pathogenicity island (cagPAI) have been found to be more virulent, with more carcinomas associated with infection by these strains. Significantly, higher levels of H. pylori-initiated chronic gastritis is characterized by the cagPAI-dependent up-regulation of proinflammatory cytokines, which are largely mediated by the transcription factor nuclear factor (NF)-κB. The goal of this work is to better define the bacterial proteins and the cellular signaling molecules involved in H. pylori-induced NF-κB activation. The H. pylori virulence factor CagA, encoded by the cagPAI, is injected into host cells via a type 4 secretion system, where it interacts with a number of different signaling pathways leading to inflammation and cell scattering. While a number of these interactions have been defined, the role of CagA in NF-κB activation and in immune response remains unclear. In this work, CagA is shown to be crucial in the activation of NF-κB by H. pylori infection. Once inside the cell, CagA utilizes host proteins to induce NF-κB activity. CagA associates with transforming growth factor β-activated kinase 1 (TAK1), a MAP kinase involved in the NF-κB, AP-1 and JNK signaling pathways, and enhances the polyubiquitination and iii activation of the kinase. This lysine 63-linked ubiquitination is mediated by E3 ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) and E2 Ubc13. These findings show that polyubiquitination of TAK1 regulates the activation of NF-κB, which in turn is used by H. pylori CagA for the H. pylori-induced inflammatory response.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2012

Author dc:creator

• Lamb, Acacia

Contributors dc:contributor

• Chen, Lin-Feng
• Shapiro, David J.
• Fratti, Rutilio A.
• Huang, Raven H.

• Helicobacter pylori
• NF-kB
• TAK1
• ubiquitination

Statement dc:rights

• Copyright 2012 Acacia Lamb

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/31951

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/31951