Differential Roles of ASK1 and TAK1 in Helicobacter pylori-Induced Cellular Responses

Abstract

The mitogen-activated protein kinase (MAPK) signaling pathway regulates various cellular functions, including those induced by Helicobacter pylori. TAK1 is an upstream MAPK kinase kinase (MAP3K) required for H. pylori-induced MAPK and NF-B activation, but it remains unclear whether other MAP3Ks are involved in H. pylori-induced cellular responses. In this study, we focused on the MAP3K ASK1, which plays a critical role in gastric tumorigenesis. In gastric epithelial cells, H. pylori activates ASK1 in a reactive oxygen species (ROS)-and cag pathogenicity island-dependent manner, and ASK1 regulates sustained JNK activation and apoptosis induced by H. pylori. In contrast, TAK1 regulates H. pylori-mediated early JNK activation and cytokine production. We also found reciprocal regulation between ASK1 and TAK1 in H. pylori-related responses, whereby inhibition of TAK1 or downstream p38 MAPK activates ASK1 through ROS production, and ASK1 suppresses TAK1 and downstream NF-B activation. We identified ROS/ASK1/JNK as a new signaling pathway induced by H. pylori, which regulates apoptotic cell death. The balance of ASK1-induced apoptosis and TAK1-induced antiapoptotic or inflammatory responses may determine the fate of epithelial cells infected with H. pylori and thus be involved in the pathogenesis of gastritis and gastric cancer.T he mitogen-activated protein kinase (MAPK) signaling pathway is involved in various cellular functions, including cell cycle, apoptosis, inflammatory responses, and differentiation (1). This pathway consists of three sequential kinases, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. More than 20 kinds of MAP3Ks regulate different and distinct functions depending on the stimuli or stresses involved (2).Apoptosis signal-regulating kinase 1 (ASK1) is a MAP3K that regulates apoptosis, immune responses, and carcinogenesis (3-5). ASK1 binds directly to thioredoxin (TRX), a reduction/oxidation regulatory protein, and intracellular reactive oxygen species (ROS) can activate ASK1 by dissociating it from TRX (6). ASK1 activates the downstream MAPKs c-Jun-N-terminal kinase (JNK) and p38 through phosphorylation of the MAP2Ks, MKK4, and MKK3. ASK1 and subsequent MAPK activation are involved in various human diseases (7, 8), and we reported previously that ASK1 plays critical roles in the development of colitis, colon cancer, liver injury, liver cancer, and gastric cancer (9-13).Gastric cancer is one of the most common cancers worldwide, and Helicobacter pylori is known to be a critical risk factor for the disease (14). It has been reported that H. pylori and its virulence factor cag pathogenicity island (PAI) activates nuclear factor-B (NF-B) and MAPK signaling through MyD88 and TAK1 activation (15)(16)(17)(18)(19)(20). The activation of these signaling pathways is important for the cytokine production or cell proliferation that leads to the development of gastric cancer (21-24). However, the relationship between H. pylori and ASK1 in epithelial cells has not been fully investigated.TAK1 positi...

Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise

“…The gastric epithelial cell lines AGS or Kato III infected with H. pylori undergo apoptosis through a mechanism involving mitochondrial depolarization caused by H 2 O 2 [49, 123–125], and this can be blocked by catalase or by antioxidants like vitamin E or N-acetylcyteine [49, 124, 125]. Further, Hayakawa et al have also described that the rapid oxidative burst of H. pylori -infected gastric epithelial cells in vitro activates the apoptosis signal-regulating kinase 1 (ASK1) that ultimately triggers c-Jun N-terminal kinase (JNK) phosphorylation and cell apoptosis [125].…”

“…Further, Hayakawa et al have also described that the rapid oxidative burst of H. pylori -infected gastric epithelial cells in vitro activates the apoptosis signal-regulating kinase 1 (ASK1) that ultimately triggers c-Jun N-terminal kinase (JNK) phosphorylation and cell apoptosis [125]. Remarkably.…”

ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney

“…Deletion of either ASK1 or TAK1 significantly reduced renal fibrosis in the obstructed kidney but had opposing effects upon cell apoptosis. ASK1 is best known for its proapoptotic role in oxygen radical-induced cell apoptosis (35,42,44), whereas TAK1 exerts an antiapoptotic action in most (but not all) cell types (5,13). Given that both ASK1 and TAK1 deletion suppress proapoptotic p38 and JNK signaling, the most likely explanation for this difference is that TAK1 deletion also suppressed NF-B signaling, which has a potent antiapoptotic action in most cell types (27).…”

Helicobacter pylori-Induced Signaling Pathways Contribute to Intestinal Metaplasia and Gastric Carcinogenesis

“…ASK1 is involved in cellular responses induced by H. pylori , such as apoptosis and cytokine production. Furthermore, ASK1 and TAK1 have reciprocal interactions and differentially regulate the activation of downstream molecules, such as JNK, p38, and NF- κ B [ 84 ].…”