Distinct Roles of Secreted HtrA Proteases from Gram-negative Pathogens in Cleaving the Junctional Protein and Tumor Suppressor E-cadherin
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Date
2012-03-23
Publication Type
Journal Article
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yes
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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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published
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Journal / series
Volume
287 (13)
Pages / Article No.
10115 - 10120
Publisher
American Society for Biochemistry and Molecular Biology
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Subject
Bacterial Pathogenesis; Campylobacter; E-cadherin; Helicobacter pylori; Protease; Gram-negative Pathogens; HtrA; Neisseria
Organisational unit
03852 - Schneider, Gisbert / Schneider, Gisbert