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The type VII secretion system of Staphylococcus aureus secretes a nuclease toxin that targets competitor bacteria

Nature Microbiology volume 2, Article number: 16183 (2016) | Download Citation

Abstract

The type VII protein secretion system (T7SS) plays a critical role in the virulence of human pathogens including Mycobacterium tuberculosis and Staphylococcus aureus. Here, we report that the S. aureus T7SS secretes a large nuclease toxin, EsaD. The toxic activity of EsaD is neutralized during its biosynthesis through complex formation with an antitoxin, EsaG, which binds to its C-terminal nuclease domain. The secretion of EsaD is dependent on a further accessory protein, EsaE, that does not interact with the nuclease domain, but instead binds to the EsaD N-terminal region. EsaE has a dual cytoplasmic/membrane localization, and membrane-bound EsaE interacts with the T7SS secretion ATPase, EssC, implicating EsaE in targeting the EsaDG complex to the secretion apparatus. EsaD and EsaE are co-secreted, whereas EsaG is found only in the cytoplasm and may be stripped off during the secretion process. Strain variants of S. aureus that lack esaD encode at least two copies of EsaG-like proteins, most probably to protect themselves from the toxic activity of EsaD secreted by esaD+ strains. In support of this, a strain overproducing EsaD elicits significant growth inhibition against a sensitive strain. We conclude that the T7SS may play unexpected and key roles in bacterial competitiveness.

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Acknowledgements

This study was supported by the UK Biotechnology and Biological Sciences Research Council (grant no. BB/H007571/1), the Medical Research Council (grants nos. G117/519 and MR/M011224/1), the Wellcome Trust (Early Postdoctoral Training Fellowship for Clinician Scientists WT099084MA to J.D.C., Investigator Award 110183/Z/15/Z to T.P. and Institutional Strategic Support Fund 105606/Z/14/Z to the University of Dundee), Tenovus Scotland (project grant no. T14/10) and a China Scholarship Council PhD studentship (to Z.C.). The authors thank G. Buchanan for constructing some of the bacterial two-hybrid clones used in this study, J. Cargill for advice regarding synthetic construct design and co-purification experiments, M. Costa for assistance with microscopy, E. Murray and P. Williams (University of Nottingham) for supplying phage ɸ11, J.-M. van Dijl (University of Groningen) for the gift of anti-TrxA antiserum, R. Bertram (University of Tübingen) for pRAB11 and F. Sargent and S. Coulthurst for discussion and advice.

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Affiliations

  1. Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK

    • Zhenping Cao
    • , M. Guillermina Casabona
    • , Holger Kneuper
    •  & Tracy Palmer
  2. Division of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK

    • James D. Chalmers

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Contributions

Z.C., M.G.C., H.K., J.D.C. and T.P. designed the experiments. Z.C., M.G.C. and H.K. carried out experimental work. Z.C., M.G.C., H.K., J.D.C. and T.P. undertook data analysis. T.P. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tracy Palmer.

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https://doi.org/10.1038/nmicrobiol.2016.183

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