title: Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin.
abstract: The periplasmic chaperone and serine protease HtrA is important for bacterial stress responses and protein quality control. Recently, we discovered that HtrA from Helicobacter pylori is secreted and cleaves E-cadherin to disrupt the epithelial barrier, but it remained unknown whether this maybe a general virulence mechanism. Here, we show that important other pathogens including enteropathogenic Escherichia coli, Shigella flexneri, and Campylobacter jejuni, but not Neisseria gonorrhoeae, cleaved E-cadherin on host cells. HtrA deletion in C. jejuni led to severe defects in E-cadherin cleavage, loss of cell adherence, paracellular transmigration, and basolateral invasion. Computational modeling of HtrAs revealed a conserved pocket in the active center exhibiting pronounced proteolytic activity. Differential E-cadherin cleavage was determined by an alanine-to-glutamine exchange in the active center of neisserial HtrA. These data suggest that HtrA-mediated E-cadherin cleavage is a prevalent pathogenic mechanism of multiple gram-negative bacteria representing an attractive novel target for therapeutic intervention to combat bacterial infections.
authors.affiliation: Division of Microbiology, University Salzburg, 5020 Salzburg, Austria.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hoy
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, 8092 Zurich, Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Geppert
authors.affiliation: School of Biomolecular and Biomedical Sciences, University College Dublin, Dublin 4, Ireland, and.
authors.forename: Manja
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, 8092 Zurich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Reisen
authors.affiliation: Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, D-33501 Bielefeld, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Plattner
authors.affiliation: Christian Doppler Laboratory for Allergy Diagnosis and Therapy, University Salzburg, 5020 Salzburg, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gadermaier
authors.affiliation: Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, D-33501 Bielefeld, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Sewald
authors.affiliation: Christian Doppler Laboratory for Allergy Diagnosis and Therapy, University Salzburg, 5020 Salzburg, Austria.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ferreira
authors.affiliation: Christian Doppler Laboratory for Allergy Diagnosis and Therapy, University Salzburg, 5020 Salzburg, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Briza
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, 8092 Zurich, Switzerland.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
authors.affiliation: School of Biomolecular and Biomedical Sciences, University College Dublin, Dublin 4, Ireland, and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Backert
authors.affiliation: Division of Microbiology, University Salzburg, 5020 Salzburg, Austria. Electronic address: silja.wessler@sbg.ac.at.
authors.forename: Silja
authors.initials: S
authors.lastname: Wessler
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000201:enzymology* / Q000235:genetics; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D006801:Humans; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D015820:Cadherins; D025521:Tumor Suppressor Proteins; D012697:Serine Endopeptidases