Abstract
Protein secretion mechanisms are essential for the virulence of most bacterial pathogens. Typhoid toxin is an essential virulence factor for Salmonella Typhi, the cause of typhoid fever in humans. This toxin is unique in that it is only produced within mammalian cells, and it must be trafficked to the extracellular space before intoxicating target cells. An essential and poorly understood aspect of this transport pathway is the secretion of typhoid toxin from the bacterium into the S. Typhi-containing vacuole. We show here that typhoid toxin secretion requires its translocation to the trans side of the peptidoglycan layer at the bacterial poles for subsequent release through the outer membrane. This translocation process depends on a specialized muramidase, the activity of which requires the localized editing of peptidoglycan by a specific ld-transpeptidase. These studies describe a protein export mechanism that is probably conserved in other bacterial species.
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Acknowledgements
The authors thank H. Rego for useful discussions, and members of the Galán laboratory for critical review of the manuscript. T.G. was supported in part by a Postdoctoral Fellowship (GE 2653/1-1) from the Deutsche Forschungsgemeinschaft (German Research Foundation). This work was supported by the National Institute of Allergy and Infectious Diseases under grant AI079022 (to J.E.G.) and the UK Medical Research Council under grant MR/N002679/1 (to W.V.).
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T.G. was involved in the design and interpretation of experiments and conducted all experiments shown except the biochemical characterization of the PG structure, which was conducted by M.P. with the supervision of W.V., and the LC–MS/MS analysis of culture supernatants, which was carried out by M.L.-T. J.E.G was involved in the design, interpretation and supervision of this study. T.G. and J.E.G. wrote the paper with comments from all authors.
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Supplementary Figures 1–14, Supplementary Tables 1 and 2.
Supplementary Data Set 1
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Supplementary Data Set 6
Data of the LC–MS/MS analysis of bacterial cell supernatants after treatment with various compounds.
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Geiger, T., Pazos, M., Lara-Tejero, M. et al. Peptidoglycan editing by a specific ld-transpeptidase controls the muramidase-dependent secretion of typhoid toxin. Nat Microbiol 3, 1243–1254 (2018). https://doi.org/10.1038/s41564-018-0248-x
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DOI: https://doi.org/10.1038/s41564-018-0248-x
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