The Helicobacter pylori type IV secretion system upregulates epithelial cortactin expression by a CagA- and JNK-dependent pathway.
Helicobacter
JNK
cancer
cortactin
pathogenesis
pathogenicity island
signalling
virulence
Journal
Cellular microbiology
ISSN: 1462-5822
Titre abrégé: Cell Microbiol
Pays: India
ID NLM: 100883691
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
18
06
2021
received:
03
04
2021
accepted:
28
06
2021
pubmed:
2
7
2021
medline:
14
1
2022
entrez:
1
7
2021
Statut:
ppublish
Résumé
Cortactin represents an important actin-binding factor, which controls actin-cytoskeletal remodelling in host cells. In this way, cortactin has been shown to exhibit crucial functions both for cell movement and tumour cell invasion. In addition, the cortactin gene cttn is amplified in various cancer types of humans. Helicobacter pylori is the causative agent of multiple gastric diseases and represents a significant risk factor for the development of gastric adenocarcinoma. It has been repeatedly shown that H. pylori manipulates cancer-related signal transduction events in infected gastric epithelial cells such as the phosphorylation status of cortactin. In fact, H. pylori modifies the activity of cortactin's binding partners to stimulate changes in the actin-cytoskeleton, cell adhesion and motility. Here we show that H. pylori infection of cultured AGS and Caco-2 cells for 24-48 hr leads to the overexpression of cortactin by 2-3 fold at the protein level. We demonstrate that this activity requires the integrity of the type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI) as well as the translocated effector protein CagA. We further show that ectopic expression of CagA is sufficient to stimulate cortactin overexpression. Furthermore, phosphorylation of CagA at the EPIYA-repeat region is not required, suggesting that this CagA activity proceeds in a phosphorylation-independent fashion. Inhibitor studies further demonstrate that the involved signalling pathway comprises the mitogen-activated protein kinase JNK (c-Jun N-terminal kinase), but not ERK1/2 or p38. Taken together, using H. pylori as a model system, this study discovered a previously unrecognised cortactin activation cascade by a microbial pathogen. We suggest that H. pylori targets cortactin to manipulate the cellular architecture and epithelial barrier functions that can impact gastric cancer development. TAKE AWAYS: Helicobacter pylori infection induces overexpression of cortactin at the protein level Cortactin upregulation requires the T4SS and effector protein CagA Ectopic expression of CagA is sufficient to stimulate cortactin overexpression Overexpression of cortactin proceeds CagA phosphorylation-independent The involved host cell signalling pathway comprises the MAP kinase JNK.
Substances chimiques
Antigens, Bacterial
0
Bacterial Proteins
0
CTTN protein, human
0
Cortactin
0
Type IV Secretion Systems
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13376Informations de copyright
© 2021 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd.
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