Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin.

The Journal of Biological Chemistry
Benjamin HoySilja Wessler

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.

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Citations

Jan 17, 2014·World Journal of Gastroenterology : WJG·Ian M Carroll, Nitsan Maharshak
Dec 21, 2012·Future Microbiology·Rebekka Steinmann, Petra Dersch
Dec 25, 2012·FEBS Letters·Angela Margarida CostaCeu Figueiredo
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Jul 17, 2015·Microbial Cell Factories·Frédéric SamazanIsabelle Poquet
May 7, 2015·BioMed Research International·Suneesh Kumar PachathundikandiSteffen Backert
Jun 3, 2016·Frontiers in Plant Science·Otilia CheregiChristiane Funk
Jun 9, 2016·Gut Pathogens·Thomas P SchmidtSilja Wessler
Jul 1, 2017·Annals of the New York Academy of Sciences·Roland BückerJörg-Dieter Schulzke
Mar 28, 2018·Cellular Microbiology·Steffen BackertSilja Wessler
Sep 6, 2013·Microbiology and Molecular Biology Reviews : MMBR·Vanessa Liévin-Le Moal, Alain L Servin
Mar 8, 2019·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·Adam L Edwinson, Madhusudan Grover

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