Distant relatives of a eukaryotic cell-specific toxin family evolved a complement-like mechanism to kill bacteria

HL Abrahamsen; TC Sanford; CE Collamore; BA Johnstone; MJ Coyne; L García-Bayona; MP Christie; JC Evans; AJ Farrand; K Flores; CJ Morton; MW Parker; LE Comstock; RK Tweten

Journal article

Distant relatives of a eukaryotic cell-specific toxin family evolved a complement-like mechanism to kill bacteria

HL Abrahamsen, TC Sanford, CE Collamore, BA Johnstone, MJ Coyne, L García-Bayona, MP Christie, JC Evans, AJ Farrand, K Flores, CJ Morton, MW Parker, LE Comstock, RK Tweten

Nature Communications | NATURE PORTFOLIO | Published : 2024

DOI: 10.1038/s41467-024-49103-5

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Abstract

Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own C..

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University of Melbourne Researchers

Bronte Johnstone Author

Michelle Christie Author

Craig Morton Author

Michael Parker Author

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Grants

Awarded by Australian Nuclear Science and Technology Organisation

Funding Acknowledgements

We thank P. Parrish for technical help in purifying proteins and Dr Sara Lawrence, who grew the first crystals of EaCDCLs. This work was supported by a US National Institutes of Health grant (NIAID) 5R37AI037657-27 to R.K.T. L.E.C. is supported by the Duchossois Family Institute and US National Institutes of Health grant (NIAID) R01AI093771. B.A.J. was the recipient of an Australian Government Research Training Program (RTP) Scholarship. This work was also supported by Australian Research Council Discovery Projects grants (DP200102871, DP230101148) to M.W.P. and C.J.M. Infrastructure support from the National Health and Medical Research Council of Australia (NHMRC) Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Program to St. Vincent's Institute are gratefully acknowledged. M.W.P. is an NHMRC Leadership Fellow (APP1194263). L.G.-B. is supported by the US National Institutes of Health grant (NIAID) K99AI167064. This research was partly undertaken at the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organization, on the MX beamlines and made use of the ACRF Detector on the MX2 beamline. Electron microscopy was performed at the Ian Holmes Imaging Center (IHIC), located at the Bio21 Molecular Science and Biotechnology Institute, and we thank the technical support of facility staff.