VE-Cadherin Cleavage by LasB Protease from Pseudomonas aeruginosa Facilitates Type III Secretion System Toxicity in Endothelial Cells
Open accessAbstract
Infection of the vascular system by Pseudomonas aeruginosa (Pa) occurs during bacterial dissemination in the body or in blood-borne infections. Type 3 secretion system (T3SS) toxins from Pa induce a massive retraction when injected into endothelial cells. Here, we addressed the role of type 2 secretion system (T2SS) effectors in this process. Mutants with an inactive T2SS were much less effective than wild-type strains at inducing cell retraction. Furthermore, secretomes from wild-types were sufficient to trigger cell-cell junction opening when applied to cells, while T2SS-inactivated mutants had minimal activity. Intoxication was associated with decreased levels of vascular endothelial (VE)-cadherin, a homophilic adhesive protein located at endothelial cell-cell junctions. During the process, the protein was cleaved in the middle of its extracellular domain (positions 335 and 349). VE-cadherin attrition was T3SS-independent but T2SS-dependent. Interestingly, the epithelial (E)-cadherin was unaffected by T2SS effectors, indicating that this mechanism is specific to endothelial cells. We showed that one of the T2SS effectors, the protease LasB, directly affected VE-cadherin proteolysis, hence promoting cell-cell junction disruption. Furthermore, mouse infection with Pa to induce acute pneumonia lead to significant decreases in lung VE-cadherin levels, whereas the decrease was minimal with T2SS-inactivated or LasB-deleted mutant strains. We conclude that the T2SS plays a pivotal role during Pa infection of the vascular system by breaching the endothelial barrier, and propose a model in which the T2SS and the T3SS cooperate to intoxicate endothelial cells.
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Tight junctions are targets of infectious agents such as Pseudomonas aeruginosa (through LasB), H. pylori (PqqE and HtrA), C. jejuni (HtrA), V. cholerae (vibrolysin), Shigella, Salmonella or pathogenic Escherichia coli (SepA).
“Tight junctions are also targets of infectious agents such as Pseudomonas aeruginosa (through LasB),132 H. pylori (PqqE and HtrA),61–63 C. jejuni (HtrA), 79,80 V. cholerae (vibrolysin),10,83 Shigella, Salmonella or pathogenic Escherichia coli (SepA).72,133”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [132]
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The emerging roles of bacterial proteases in intestinal diseases
Caminero, A., Guzman, M., Libertucci, J., & Lomax, A. E. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2181922 · Cited by 92 · see citing works
- Authors
- Golovkine, G., Faudry, E., Bouillot, S., Voulhoux, R., Attrée, I., & Huber, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Huber, Philippe
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-03-13
- Volume
- 10
- Issue
- 3
- Pages
- e1003939
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3953407
- OpenAlex
- W2165188429
- Cited by
- 78
- References
- 43
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 4
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Fondation Innovations en Infectiologie
- Centre National de la Recherche Scientifique
- Université Joseph Fourier
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Vibrio bacteria research studies
- Keywords
- Pseudomonas aeruginosa, type II secretion system, type III secretion system, VE-cadherin, E-cadherin, endothelial cell retraction, endothelial barrier, bacterial virulence factors, vascular infection, acute pneumonia, secretome
- MeSH terms
- Cadherin 5, Animals, Bacterial Proteins, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Fluorescent Antibody Technique, Humans, Male, Metalloendopeptidases, Mice, Inbred BALB C, Pseudomonas Infections, Blotting, Western, Antigens, CD, Cadherins, Mice, Bacterial Secretion Systems
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