Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2016; 22(48): 10566-10574
Published online Dec 28, 2016. doi: 10.3748/wjg.v22.i48.10566
Helicobacter pylori inhibits the cleavage of TRAF1 via a CagA-dependent mechanism
Xiu-Kun Wan, Sheng-Ling Yuan, Yan-Chun Wang, Hao-Xia Tao, Wei Jiang, Zhang-Yan Guan, Cheng Cao, Chun-Jie Liu
Xiu-Kun Wan, Sheng-Ling Yuan, Yan-Chun Wang, Hao-Xia Tao, Wei Jiang, Zhang-Yan Guan, Cheng Cao, Chun-Jie Liu, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100071, China
Author contributions: Liu CJ designed the research; Wan XK performed the majority of experiments and analyzed the data; Yuan SL, Wang YC, Tao HX, Jiang W, Guan ZY and Cao C participated equally in the research; Wan XK and Liu CJ wrote and revised the paper.
Supported by Ministry of Science and Technology of the People’s Republic of China and Major New Drug Creation, No. 2012ZX09301003-001-005.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at liucj@nic.bmi.ac.cn. All participants provided informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Chun-Jie Liu, Professor, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, China. liucj@nic.bmi.ac.cn
Telephone: + 86-10-66948834 Fax: + 86-10-66948815
Received: June 28, 2016
Peer-review started: June 29, 2016
First decision: August 19, 2016
Revised: September 5, 2016
Accepted: October 10, 2016
Article in press: October 10, 2016
Published online: December 28, 2016
Abstract
AIM

To study the impact on cleavage of tumor necrosis factor receptor-associated factor 1 (TRAF1) regulated by Helicobacter pylori (H. pylori).

METHODS

Cleavage of TRAF1 was detected by western blotting in the human gastric cancer cell line AGS following treatment with an apoptosis inducer. Cleavage of TRAF1 mediated by caspase was examined in vitro using specific caspase inhibitors. The effect of the COOH-terminal TRAF1 fragment on gastric cell apoptosis during H. pylori infection was measured using flow cytometry. The impact of H. pylori infection on TRAF1 cleavage was detected in the presence of apoptosis inducer. The roles of H. pylori virulence factors that may regulate TRAF1 cleavage were analyzed using isogenic cagA-, vacA- and cagE-null mutants.

RESULTS

TRAF1 was found to be cleaved in AGS cells treated with the apoptosis inducer, and caspase-8 was the major caspase involved in the cleavage of TRAF1. The COOH-terminal TRAF1 fragment significantly induced cell apoptosis (P < 0.05) as well as promoted H. pylori-induced cell apoptosis (P < 0.05). H. pylori infection was found to significantly inhibit the cleavage of TRAF1 and to inhibit the activation of caspase-8 in the presence of the apoptosis inducer at specific infection times and different cell/bacteria ratios. We also found that the effects of cagE- and cagA-null mutants on the inhibition of TRAF1 cleavage and activation of caspase-8 were significantly attenuated, compared with wild-type H. pylori, in the presence of the apoptosis inducer, showing that the virulence factor CagA was mainly involved in the inhibition of TRAF1 cleavage.

CONCLUSION

H. pylori infection significantly inhibits the cleavage of TRAF1 via a CagA-dependent mechanism, which would increase the relative amounts of full-length TRAF1 and exert an antiapoptotic effect on H. pylori-infected cells.

Keywords: Helicobacter pylori, Tumor necrosis factor receptor-associated factor 1, CagA, Cleavage, Apoptosis

Core tip: We report our first results from a study of Helicobacter pylori (H. pylori)-mediated tumor necrosis factor receptor-associated factor 1 (TRAF1) cleavage. The impact of H. pylori infection and its virulence factors on TRAF1 cleavage were detected in the presence of an apoptosis inducer. This study demonstrates, for the first time, that the cleavage of TRAF1 and the activation of caspase-8 were significantly inhibited by H. pylori infection in the presence of an apoptosis inducer. In addition, the virulence factor CagA was mainly involved in the inhibition of TRAF1 cleavage.