Cargando…
A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells
The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extrac...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627848/ https://www.ncbi.nlm.nih.gov/pubmed/31185677 http://dx.doi.org/10.3390/cancers11060801 |
_version_ | 1783434829166018560 |
---|---|
author | Bravo, Jimena Díaz, Paula Corvalán, Alejandro H. Quest, Andrew F.G. |
author_facet | Bravo, Jimena Díaz, Paula Corvalán, Alejandro H. Quest, Andrew F.G. |
author_sort | Bravo, Jimena |
collection | PubMed |
description | The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer. |
format | Online Article Text |
id | pubmed-6627848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66278482019-07-23 A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells Bravo, Jimena Díaz, Paula Corvalán, Alejandro H. Quest, Andrew F.G. Cancers (Basel) Article The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer. MDPI 2019-06-10 /pmc/articles/PMC6627848/ /pubmed/31185677 http://dx.doi.org/10.3390/cancers11060801 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bravo, Jimena Díaz, Paula Corvalán, Alejandro H. Quest, Andrew F.G. A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title | A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title_full | A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title_fullStr | A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title_full_unstemmed | A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title_short | A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells |
title_sort | novel role for helicobacter pylori gamma-glutamyltranspeptidase in regulating autophagy and bacterial internalization in human gastric cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627848/ https://www.ncbi.nlm.nih.gov/pubmed/31185677 http://dx.doi.org/10.3390/cancers11060801 |
work_keys_str_mv | AT bravojimena anovelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT diazpaula anovelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT corvalanalejandroh anovelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT questandrewfg anovelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT bravojimena novelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT diazpaula novelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT corvalanalejandroh novelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells AT questandrewfg novelroleforhelicobacterpylorigammaglutamyltranspeptidaseinregulatingautophagyandbacterialinternalizationinhumangastriccells |