Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA

Schmidt TP, Perna AM, Fugmann T, Böhm M, Hiss J, Haller S, Goetz C, Tegtmeyer N, Hoy B, Rau T, Neri D, Backert S, Schneider G, Wessler S (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 6

Pages Range: 23264

DOI: 10.1038/srep23264

Abstract

The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions.

Authors with CRIS profile

Manja Böhm Lehrstuhl für Mikrobiologie Nicole Tegtmeyer-Backert Lehrstuhl für Mikrobiologie Steffen Backert Lehrstuhl für Mikrobiologie

Involved external institutions

École Polytechnique Fédérale de Lausanne (EPFL) CH Switzerland (CH) Universität Salzburg (Paris Lodron Universität Salzburg) AT Austria (AT) Philochem AG CH Switzerland (CH)

How to cite

APA:

Schmidt, T.P., Perna, A.M., Fugmann, T., Böhm, M., Hiss, J., Haller, S.,... Wessler, S. (2016). Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Scientific Reports, 6, 23264. https://doi.org/10.1038/srep23264

MLA:

Schmidt, Thomas P., et al. "Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA." Scientific Reports 6 (2016): 23264.

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