Distinct Roles of Secreted HtrA Proteases from Gram-negative Pathogens in Cleaving the Junctional Protein and Tumor Suppressor E-cadherin

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 ge...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2012-03, Vol.287 (13), p.10115-10120
Main Authors: Hoy, Benjamin, Geppert, Tim, Boehm, Manja, Reisen, Felix, Plattner, Patrick, Gadermaier, Gabriele, Sewald, Norbert, Ferreira, Fatima, Briza, Peter, Schneider, Gisbert, Backert, Steffen, Wessler, Silja
Format: Article
Language:English
Subjects:
Bacterial Pathogenesis
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Caco-2 Cells
Cadherins - genetics
Cadherins - metabolism
Campylobacter
E-cadherin
Gram-Negative Bacteria - enzymology
Gram-Negative Bacteria - genetics
Gram-Negative Bacterial Infections - enzymology
Gram-Negative Bacterial Infections - genetics
Gram-Negative Bacterial Infections - therapy
Gram-negative Pathogens
Helicobacter pylori
HtrA
Humans
Microbiology
Neisseria
Protease
Proteolysis
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. The function of HtrA proteases in bacterial infections is widely unknown. Secreted HtrA from various bacterial pathogens exhibits a conserved specificity for cleavage of E-cadherin. HtrA-mediated E-cadherin cleavage is a prevalent novel mechanism in bacterial pathogenesis. HtrA activity plays a direct role in the pathogenesis of different bacteria.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C111.333419