AUTHOR=Li Na , Tang Bin , Jia Yin-ping , Zhu Pan , Zhuang Yuan , Fang Yao , Li Qian , Wang Kun , Zhang Wei-jun , Guo Gang , Wang Tong-jian , Feng You-jun , Qiao Bin , Mao Xu-hu , Zou Quan-ming 

TITLE=Helicobacter pylori CagA Protein Negatively Regulates Autophagy and Promotes Inflammatory Response via c-Met-PI3K/Akt-mTOR Signaling Pathway

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=7

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2017.00417

DOI=10.3389/fcimb.2017.00417

ISSN=2235-2988

ABSTRACT=<p>Cytotoxin-associated-gene A (CagA) of <italic>Helicobacter pylori</italic> (<italic>H. pylori</italic>) is a virulence factor that plays critical roles in <italic>H. pylori</italic>-induced gastric inflammation. In the present study, gastric biopsies were used for genotyping <italic>cagA</italic> and <italic>vacA</italic> genes, determining the autophagic activity, and the severity of gastric inflammation response. It was revealed that autophagy in gastric mucosal tissues infected with <italic>cagA</italic><sup>+</sup><italic>H. pylori</italic> strains was lower than the levels produced by <italic>cagA</italic><sup>−</sup><italic>H. pylori</italic> strains, accompanied with accumulation of SQSTM1 and decreased LAMP1 expression. <italic>In vitro</italic>, deletion mutant of <italic>cagA</italic> gene resulted in increased autophagic activity, and decreased expression of SQSTM1 and cytokines, whereas over-expression of CagA down-regulated the starvation-induced autophagy, and induced more production of the cytokines. Moreover, the production of the cytokines was increased by inhibition of autophagy, but decreased by enhancement of autophagy. Deletion of CagA decreased the ability to activate Akt kinase at Ser-473 site and increased autophagy. c-Met siRNA significantly affected CagA-mediated autophagy, and decreased the level of p-Akt, p-mTOR, and p-S6. Both c-Met siRNA and MK-2206 could reverse inflammatory response. <italic>H. pylori</italic> CagA protein negatively regulates autophagy and promotes the inflammation in <italic>H. pylori</italic> infection, which is regulated by c-Met-PI3K/Akt-mTOR signaling pathway activation.</p>