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The junctional integrity of epithelial cells is modulated by Pseudomonas aeruginosa quorum sensing molecule through phosphorylation-dependent mechanisms
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
2009 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, no 2, 313-326 p.Article in journal (Refereed) Published
Abstract [en]

In Pseudomonas aeruginosa, cell-cell Communication based on acyl-homoserine lactone (HSL) quorum sensing molecules is known to coordinate the production of virulence factors and biofilms by the bacterium. Incidentally, these bacterial signals can also modulate mammalian cell behaviour. We report that 3O-C-12-HSL can disrupt adherens junctions in human epithelial Caco-2 cells as evidenced by a reduction of the expression and distribution of E-cadherin and beta-catenin. Using co-immunoprecipitation we also found that P. aeruginosa 3O-C-12-HSL-treatment resulted in tyrosine hyperphosphorylation of E-cadherin, beta-catenin, occludin and ZO-1. Similarly, serine and threonine residues of E-cadherin and ZO-1 became more phosphorylated after 3O-C-12-HSL treatment. On the contrary, occludin and beta-catenin underwent dephosphorylation on serine and threonine residues after exposition of 3O-C-12-HSL. These changes in the phosphorylation state were paralleled by alteration in the Structure of junction complexes and increased paracellular permeability. Moreover, pre-treatment of the Caco-2 cells with protein phosphatase and kinase inhibitors prevented 3O-C-12-HSL-induced changes in paracellular permeability and interactions between occludin-ZO-1 and the E-cadherin-beta-catenin. These findings clearly suggest that an alteration in the phosphorylation status of junction proteins are involved in the changes in cell junction associations and enhanced paracellular permeability, and that bacterial signals are indeed sensed by the host cells.

Place, publisher, year, edition, pages
2009. Vol. 315, no 2, 313-326 p.
Keyword [en]
Quorum sensing, Pseudomonas aeruginosa, Acyl-homoserine lactone, Epithelial barrier, Adherens and tight junctions, Protein phosphorylations/dephosphorylations
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16627DOI: 10.1016/j.yexcr.2008.10.044OAI: oai:DiVA.org:liu-16627DiVA: diva2:159539
Available from: 2009-02-08 Created: 2009-02-06 Last updated: 2015-05-28Bibliographically approved
In thesis
1. Synthesis of Substituted Alkanethiols Intended forProtein Immobilization: Chelate Associated Photochemistry (CAP)
Open this publication in new window or tab >>Synthesis of Substituted Alkanethiols Intended forProtein Immobilization: Chelate Associated Photochemistry (CAP)
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

The first and main part of this thesis is focused on the design and synthesis of photo-activableand metal chelating alkanethiols. Chelate associated photochemistry (CAP) is a novel conceptof combining two well-known protein (ligand) immobilization strategies to obtain a sensorsurface of covalently bound ligand with defined orientation. This includes nitrilotriacetic acid(NTA) which is used to capture and pre-orientate histidine-tagged proteins to the sensorsurface, followed by UV activation of a neighboring photo-crosslinking agent, benzophenone(BP), to covalently bind the ligand in this favorable orientation. Our results (paper 1) indicatethat up to 55% more activity of the ligand is achieved with the CAP concept compared to theactivity of the randomly oriented ligand (immobilized only by BP). This also yields a surfacethat is more robust compared to if only NTA is used. The photo cross-linking withbenzophenone (BP) adduct is limited to a distance range of 3Å, it is therefore favorable tocapture the ligand before reacting with surface bound BP-adduct. The surface consists of anexcess of ethylene glycols (known for its protein-repellent properties) to prevent non-specificprotein binding, thereby increase the specificity of the sensor surface. With this obtainedsurface chemistry we hope to contribute to the development of large-scale screening systemsand microarrays based on His-tagged labeled biomolecules. This will be used in a number ofapplications such as proteomics-related applications, including drug discovery, the discoveryof lead compounds and characterization of protein-protein interactions.

The second part of this thesis describes the effect of the synthetic N-(3-oxododecanoyl)-Lhomoserinelactone (30-C12-HSL) on eukaryotic cells. 30-C12-HSL is a natural occurringsignal substance in the bacterium Pseudomonas aeruginosa, and this signal molecule isinvolved in the regulation of bacterial growth. Pseudomonas aeruginosa has been consideredas a common cause of infections in hospitals, especially in patients with compromisedimmune systems. Since the 30-C12-HSL can diffuse freely cross the cell membranes, it isexpected to have influence on the host cell behaviour. Herein, we study how the eukaryoticcells respond to the bacterial signal molecule, 30-C12-HSL. Our results (paper 2) indicatethat 30-C12-HSL disrupt the adherens junctions in human epithelial cells. The disruption iscaused by a hyperphosphorylation of the adherens junction proteins (protein complexbetween epithelial tissues). This suggests the bacterial signals are sensed by that the host cells.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 26 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1411
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-20648 (URN)LIU-TEK-LIC-2009:19 (Local ID)978-91-7393-540-1 (ISBN)LIU-TEK-LIC-2009:19 (Archive number)LIU-TEK-LIC-2009:19 (OAI)
Presentation
2009-10-02, Jordan-Fermi, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:00 (English)
Opponent
Supervisors
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2009-09-16Bibliographically approved

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Vikström, ElenaBui, LanKonradsson, PeterMagnusson, Karl-Eric

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