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The Helicobacter pylori type IV secretion system upregulates epithelial cortactin expression by a CagA- and JNK-dependent pathway.
Cellular Microbiology 2021 July 2
Cortactin represents an important actin-binding factor, which controls actin-cytoskeletal remodeling in host cells. In this way, cortactin has been shown to exhibit crucial functions both for cell movement and tumor 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 hours 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 signaling 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 unrecognized 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. This article is protected by copyright. All rights reserved.
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