Helicobacter pylori infection induces STAT3 phosphorylation on Ser727 and autophagy in human gastric epithelial cells and mouse stomach

Abstract

Helicobacter pylori (H. pylori) infection is considered as one of the principal risk factors of gastric cancer. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated gastric carcinogenesis. In the canonical STAT3 pathway, phosphorylation of STAT3 on Tyr705 is a major event of STAT3 activation. However, recent studies have demonstrated that STAT3 phosphorylated on Ser727 has an independent function in mitochondria. In the present study, we found that human gastric epithelial AGS cells infected with H. pylori resulted in localization of STAT3 phosphorylated on Ser727 (P-STAT3Ser727), predominantly in the mitochondria. Notably, H. pylori-infected AGS cells exhibited the loss of mitochondrial integrity and increased expression of the microtubule-associated protein light chain 3 (LC3), the autophagosomal membrane-associated protein. Treatment of AGS cells with a mitophagy inducer, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), resulted in accumulation of P-STAT3Ser727 in mitochondria. In addition, the elevated expression and mitochondrial localization of LC3 induced by H. pylori infection were attenuated in AGS cells harboring STAT3 mutation defective in Ser727 phosphorylation (S727A). We also observed that both P-STAT3Ser727 expression and LC3 accumulation were increased in the mitochondria of H. pylori-inoculated mouse stomach.

Bridging the gap – a new role for STAT3 in TLR4‐mediated metabolic reprogramming

“…Here, STAT3 associates with various components of the electron transport chain (ETC), enhancing ETC complex activity 16 . Interestingly, a recent study has found that mitochondrial STAT3 phosphorylated at Ser727 induced autophagy in human gastric epithelial cells when infected with Helicobacter pylori , 17 expanding the list of the potential functions of mitochondrial STAT3. As a well‐described transcription factor, STAT3 could possibly also directly regulate mitochondrial gene expression.…”

Autophagy in Gastric Mucosa: The Dual Role and Potential Therapeutic Target

“…The signal transducer and activator of transcription 3 (STAT3) is an important transcription factor of the JAK/STAT signal pathway, mediating the expression of various genes [ 56 ]. H. pylori infection induced phosphorylation of STAT3 on Ser727, which led to increased autophagy and mitochondrial damage [ 38 ]. Since H. pylori cannot be cocultured with cells for a long time, H. pylori lysates were used insteading of living bacteria to coculture with gastric epithelial cells for a long time to simulate the regulatory effects of persistent infection on cells.…”

Role of autophagy in gastric carcinogenesis

“…The resultant suppressive autophagy allows the intracellular oxidative stress and nucleic acid alterations to induce malignant mutations. Recently, Piao et al [ 96 ] revealed that H. pylori- I modifies the function of the signal transducer and STAT3 by phosphorylating its Ser727. Thus a perpetual mitophagy is mediated and promotes gastritis and carcinogenesis[ 96 ].…”

“…Recently, Piao et al [ 96 ] revealed that H. pylori- I modifies the function of the signal transducer and STAT3 by phosphorylating its Ser727. Thus a perpetual mitophagy is mediated and promotes gastritis and carcinogenesis[ 96 ].…”