The Helicobacter pylori type IV secretion system upregulates epithelial cortactin expression by a CagA‐ and JNK‐dependent pathway. (16th July 2021)

• Record Type: Journal Article
• Authors: Sharafutdinov, Irshad; Backert, Steffen; Tegtmeyer, Nicole
• Is Part Of: Cellular microbiology. Volume 23:Number 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-16
• Subjects: cancer -- cortactin -- Helicobacter -- JNK -- pathogenesis -- pathogenicity island -- signalling -- virulence; Microbiology -- Periodicals; Cytology -- Periodicals; Host-parasite relationships -- Periodicals; Microbiology -- Periodicals; Cells -- Periodicals; Microbiologie -- Périodiques; Microbiologie; Relation hôte-parasite; Cytologie; Cellule; Réponse cellulaire; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); 579.05
• DOI: 10.1111/cmi.13376
• Languages: English
• ISSNs: 1462-5814

Abstract

Abstract: 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 ( cag PAI) 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 Abstract : Helicobacter pylori manipulates cancer‐related signal transduction events in infected gastric epithelial cells such as the phosphorylation status of the actin‐binding protein cortactin and cortactin overexpression by about 2–3 fold. Cortactin overexpression depends on the integrity of the type IV secretion system and the translocated effector protein CagA. We propose that overexpression of cortactin is based both on upregulated mRNA expression and enhanced protein stability requiring the indicated pathways to mitogen‐activated protein kinase JNK, paxillin, FAK and others, which together may have an impact on gastric cancer development.