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YopK of Yersinia pseudotuberculosis controls translocation of Yop effectors across the eukaryotic cell membrane
Department of Microbiology, National Defence Research Establishment, Umeå, Sweden and the Department of Cell and Molecular Biology, Umeå University, Umeå, Sweden.
Department of Cell and Molecular Biology, Umeå University, Umeå, Sweden.
Department of Cell and Molecular Biology, Umeå University, Umeå, Sweden.
Department of Cell and Molecular Biology, Umeå University, Umeå, Sweden.
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1997 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 24, no 1, 73-91 p.Article in journal (Refereed) Published
Abstract [en]

Introduction of anti-host factors into eukaryotic cells by extracellular bacteria is a strategy evolved by several Gram-negative pathogens. In these pathogens, the transport of virulence proteins across the bacterial membranes is governed by closely related type III secretion systems. For pathogenic Yersinia, the protein transport across the eukaryotic cell membrane occurs by a polarized mechanism requiring two secreted proteins, YopB and YopD. YopB was recently shown to induce the formation of a pore in the eukaryotic cell membrane, and through this pore, translocation of Yop effectors is believed to occur (Håkansson et al., 1996b). We have previously shown that YopK of Yersinia pseudotuberculosis is required for the development of a systemic infection in mice. Here, we have analysed the role of YopK in the virulence process in more detail. A yopK-mutant strain was found to induce a more rapid YopE-mediated cytotoxic response in HeLa cells as well as in MDCK-1 cells compared to the wild-type strain. We found that this was the result of a cell-contact-dependent increase in translocation of YopE into HeLa cells. In contrast, overexpression of YopK resulted in impaired translocation. In addition, we found that YopK also influenced the YopB-dependent lytic effect on sheep erythrocytes as well as on HeLa cells. A yopK-mutant strain showed a higher lytic activity and the induced pore was larger compared to the corresponding wild-type strain, whereas a strain overexpressing YopK reduced the lytic activity and the apparent pore size was smaller. The secreted YopK protein was found not to be translocated but, similar to YopB, localized to cell-associated bacteria during infection of HeLa cells. Based on these results, we propose a model where YopK controls the translocation of Yop effectors into eukaryotic cells.

Place, publisher, year, edition, pages
1997. Vol. 24, no 1, 73-91 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-80196DOI: 10.1046/j.1365-2958.1997.3211681.xOAI: oai:DiVA.org:liu-80196DiVA: diva2:546116
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Perturbation of the epithelial barrier by enteric pathogens
Open this publication in new window or tab >>Perturbation of the epithelial barrier by enteric pathogens
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gastrointestinal infections in humans have been associated with a number of diseased condition, including stomach ulcers, gastroenteritis, Crohn's disease, and rheumatic arthritis. Such infections often cause altered intestinal permeability through perturbation of the tight junctions that hold epithelial cells together. The objective of the present studies was to detennine whether the enteric pathogens Salmonella, Yersinia, and Rotavirus can disrupt the integrity of the epithelial barrier, and, if so, how this is achieved. Another aim was to elucidate regulation of the epithelial batrier in relation to the structure of the cytoskeleton.

To accomplish these goals, we assessed the mechanism of enhanced cytotoxicity of Yersinia YopE and the response to this protein by its target in the epithelial bartier, both of which require contact between the bacteria and the eukaryotic cells. YopK appeared to control Yop effector delivery by regulating the size of the translocation pore, and enhanced translocation was accompanied by decreased transepithelial resistance and disruption of barrier function. We also examined the interaction of Yersinia with polarized MDCK cells to detemrine the target of these bacteria. We found that wild-type Yersinia adhered apically to the tight junction areas, and, in adjacent cells, these contact points displayed ß1 integrins and tight junction proteins that allowed localized invasin-mediated binding and translocation of cytotoxins. Studying signal transduction pathways involved in the disruption of barrier function by Salmonella typhimurium, we found that infection with the wild-type strain increased the level of activated. Rac1 and Cdc42 small G-proteins and caused them to accumulate apically in MDCK cells, and this was prevented by appropriate inhibitors. Activation of these proteins was a prerequisite of disruption of barrier integrity by S. typhimurium. We also considered specific effects of the rota virus non-structural protein NSP4 on the function of tight junctions. NSP4 has been desctibed as the first viral enterotoxin, and we found that incubation of noncontluent MDCK-1 cells with NSP4 prevented development of the permeability barrier, as well as lateral targeting of the tight junction-associated zonula occludence-1 protein.

In conclusion, our results provide strong evidence that the studied pathogens perturb the epithelial barrier by binding to specific cell receptors to deliver cytotoxins (Yesinia); by interfering with cell signaling pathways (Salmonella); and by impairing normal formation of tight junctions (NSP4).

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 702
Keyword
enteric pathogens: signal transduction, barrier function
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28644 (URN)13800 (Local ID)91-7373-146-3 (ISBN)13800 (Archive number)13800 (OAI)
Public defence
2001-12-03, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
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Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-11-22Bibliographically approved

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Tafazoli, FaridehMagnusson, Karl-Eric

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