Abstract
Horizontal gene transfer events were crucial in the emergence of multicellular life. A striking example is the acquisition of Teneurins, putative surface-exposed toxins in bacteria that function as cell adhesion receptors in metazoan neuronal development. Here, we demonstrate the evolutionary relationships between metazoan and bacterial Teneurins. We use cryogenic electron microscopy and bioinformatic analysis to show that bacterial Teneurins harbour a toxic protein in a proteinaceous shell. They are rare but widely distributed across bacterial taxa and are predominantly seen in species with complex social behaviours, suggesting roles in cell-to-cell interaction. This work confirms that metazoan Teneurins are repurposed bacterial toxins that have evolved to be essential mediators of intercellular communication in all advanced nervous systems. Their acquisition was a key event in the evolution of metazoans.
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Data availability
The cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession codes EMD-52847 (BiTLP); and EMD-71831 (BiTLPFL). The atomic coordinates have been deposited in the Protein Data Bank (PDB) under accession codes 9IFO (BiTLP); and 9PT5 (BiTLPFL). The source data underlying Figs. 2, 3b and e, 4d and Supplementary Fig. 6c are provide as Source Data files. Unedited gels and Western blots are shown in Supplementary Fig. 8. Molecular dynamics trajectories are available from the corresponding authors upon request. Source data are provided with this paper.
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Acknowledgements
We acknowledge the Central Oxford Structural Molecular Imaging Center (COSMIC) electron microscopy where the cryo-EM data of BiTLP was collected. We also thank Dr Joseph Caesar for support with data processing. We would also like to acknowledge Australian Microscopy and Microanalysis Research Facility at the Center for Microscopy and Microanalysis located at the University of Queensland where the data for BiTLPFL is collected. We also thank Professor Steve Kelly for his valuable help and advice on the phylogenetic tree inference. We also give thanks to the Fribourg Lab for supplying the petMCN vector used to clone Bacillus inaquosorum TLP, and to Dr. Valentine Lagage and Dr. Diviya Choudhary for providing the pBAD vector used to clone all bacterial TLP CTD and immunity genes. We finally thank the Dean lab for providing us with the Alphafold model of Bacillus inaquosorum TLP. F.R. was funded by the Browne research fellowship, the Queen’s college Oxford. J.B. is funded by a Wellcome Trust Biomedical Resource Grant (number 218205/Z/19/Z, PubMLST: Disseminating and exploiting bacterial diversity data for public health benefit). Research in the E.S. lab was supported by the Wellcome Trust (202827/Z/16/Z and 226647/Z/22/Z) and the EMBO Young Investigator Programme.
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F.R. and E.S. conceptualized the study and designed the experiments. F.R. and C.M.R. performed the biochemical experiments. J.C.Z. and Y.S.L. performed the structural biology experiments. J.C.Z. and L.B. established and implemented the cryo-EM methodology in the laboratory. F.R., E.S., K.E.O., and E.L. built and refined the BiTLP model, while Y.S.L. and M.J.L. built and refined the BiTLPFL model. J.B. performed the bioinformatic analyses. J.S. performed the microscopy experiments. A.S. and M.C. performed the structural predictions and molecular dynamics simulations. F.R., J.S., A.S., J.C.Z. and J.B. analysed the data. F.R., J.S., A.S., J.B., C.M.R., Y.S.L., M.J.L., J.S.L., C.K., M.C., M.C.J.M., and E.S. wrote the manuscript.
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Raoelijaona, F., Szczepaniak, J., Schahl, A. et al. Ancestral neuronal receptors are bacterial accessory toxins. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69246-x
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DOI: https://doi.org/10.1038/s41467-026-69246-x
