Cortactin-dependent control of Par1b-regulated epithelial cell polarity in Helicobacter infection
Irshad Sharafutdinov,
Aileen Harrer,
Mathias Müsken,
Klemens Rottner,
Heinrich Sticht,
Christian Täger,
Michael Naumann,
Nicole Tegtmeyer,
Steffen Backert
Affiliations
Irshad Sharafutdinov
Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91058, Erlangen, Germany
Aileen Harrer
Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91058, Erlangen, Germany
Mathias Müsken
Central Facility for Microscopy, Helmholtz Centre for Infection Research, D-38124, Braunschweig, Germany
Klemens Rottner
Department of Cell Biology, Helmholtz Centre for Infection Research, D-38124, Braunschweig, Germany; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, D-38106, Braunschweig, Germany
Heinrich Sticht
Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany
Christian Täger
Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, D-39120, Magdeburg, Germany
Michael Naumann
Otto von Guericke University, Institute of Experimental Internal Medicine, Medical Faculty, D-39120, Magdeburg, Germany
Nicole Tegtmeyer
Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91058, Erlangen, Germany
Steffen Backert
Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91058, Erlangen, Germany; Corresponding author.
Cell polarity is crucial for gastric mucosal barrier integrity and mainly regulated by polarity-regulating kinase partitioning-defective 1b (Par1b). During infection, the carcinogen Helicobacter pylori hijacks Par1b via the bacterial oncoprotein CagA leading to loss of cell polarity, but the precise molecular mechanism is not fully clear. Here we discovered a novel function of the actin-binding protein cortactin in regulating Par1b, which forms a complex with cortactin and the tight junction protein zona occludens-1 (ZO-1). We found that serine phosphorylation at S405/418 and the SH3 domain of cortactin are important for its interaction with both Par1b and ZO-1. Cortactin knockout cells displayed disturbed Par1b cellular localization and exhibited morphological abnormalities that largely compromised transepithelial electrical resistance, epithelial cell polarity, and apical microvilli. H. pylori infection promoted cortactin/Par1b/ZO-1 abnormal interactions in the tight junctions in a CagA-dependent manner. Infection of human gastric organoid-derived mucosoids supported these observations. We therefore hypothesize that CagA disrupts gastric epithelial cell polarity by hijacking cortactin, and thus Par1b and ZO-1, suggesting a new signaling pathway for the development of gastric cancer by Helicobacter.
