| 1. |
- Holmström, Anna, et al.
(författare)
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YopK of Yersinia pseudotuberculosis controls translocation of Yop effectors across the eukaryotic cell membrane
- 1997
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 24:1, s. 73-91
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Persson, Cathrine, et al.
(författare)
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Localization of the Yersinia PTPase to focal complexes is an important virulence mechanism
- 1999
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Ingår i: Molecular Microbiology. - : Wiley-Blackwell Publishing Inc.. - 0950-382X .- 1365-2958. ; 33:4, s. 828-838
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Tidskriftsartikel (refereegranskat)abstract
- The protein tyrosine phosphatase YopH, produced by the pathogen Yersinia pseudotuberculosis, is an essential virulence determinant involved in antiphagocytosis. Upon infection, YopH is translocated into the target cell, where it recognizes focal complexes. Genetic analysis revealed that YopH harbours a region that is responsible for specific localization of this PTPase to focal complexes in HeLa cells and professional phagocytes. This region is a prerequisite for blocking an immediate-early Yersinia-induced signal within target cells. The region is also essential for antiphagocytosis and virulence, illustrating the biological significance of localization of YopH to focal complexes during Yersinia infection. These results also indicate that focal complexes play a role in the general phagocytic process.
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| 3. |
- Bednarska, Natalia G., et al.
(författare)
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Protein aggregation as an antibiotic design strategy
- 2016
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Ingår i: Molecular Microbiology. - : WILEY-BLACKWELL. - 0950-382X .- 1365-2958. ; 99:5, s. 849-865
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Tidskriftsartikel (refereegranskat)abstract
- Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.
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