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Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses

Yoku Hayakawa1, Yoshihiro Hirata, Hiroto Kinoshita

  • 1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Infection and Immunity
|October 2, 2013
PubMed

Insights

Helicobacter pylori infection activates the ASK1 (apoptosis signal-regulating kinase 1) pathway, leading to sustained JNK activation and apoptosis in gastric cells. This pathway balances with TAK1 to influence cell fate and disease development.

Area of Science:

  • Cellular biology
  • Molecular signaling pathways
  • Microbiology

Background:

  • Mitogen-activated protein kinase (MAPK) pathways are crucial for cellular functions.
  • Helicobacter pylori (H. pylori) infection triggers MAPK signaling.
  • The role of specific MAP3K (MAPK kinase kinase) family members, beyond TAK1, in H. pylori responses is not fully understood.

Purpose of the Study:

  • To investigate the involvement of MAP3K ASK1 (apoptosis signal-regulating kinase 1) in H. pylori-induced cellular responses.
  • To elucidate the signaling mechanisms by which ASK1 regulates H. pylori-induced apoptosis.
  • To explore the interplay between ASK1 and TAK1 in H. pylori infection.

Main Methods:

  • Utilized gastric epithelial cells for in vitro studies.
  • Investigated H. pylori-induced activation of ASK1, JNK, and NF-κB.
  • Assessed the roles of reactive oxygen species (ROS) and the cag pathogenicity island.
  • Employed TAK1 and p38 MAPK inhibition to study reciprocal regulation.

Main Results:

  • H. pylori activates ASK1 in a ROS- and cag pathogenicity island-dependent manner.
  • ASK1 mediates sustained JNK activation and apoptosis induced by H. pylori.
  • TAK1 regulates early JNK activation and cytokine production.
  • Reciprocal regulation exists: TAK1 inhibition activates ASK1 via ROS, and ASK1 suppresses TAK1/NF-κB.
  • Identified a novel ROS/ASK1/JNK signaling axis regulating H. pylori-induced apoptosis.

Conclusions:

  • The ROS/ASK1/JNK pathway is a newly identified signaling cascade in H. pylori infection, controlling apoptotic cell death.
  • The balance between ASK1-driven apoptosis and TAK1-driven anti-apoptotic/inflammatory responses dictates epithelial cell fate during H. pylori infection.
  • This balance is implicated in the pathogenesis of gastritis and gastric cancer.

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