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Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal

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  • Mabel Deladem Tettey

    (Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh)

  • Federico Rojas

    (Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh
    Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University)

  • Keith R. Matthews

    (Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh)

Abstract

Trypanosomes causing African sleeping sickness use quorum-sensing (QS) to generate transmission-competent stumpy forms in mammalian hosts. This density-dependent process is signalled by oligopeptides that stimulate the signal transduction pathway leading to stumpy formation. Here, using mass spectrometry analysis, we identify peptidases released by trypanosomes and, for 12 peptidases, confirm their extracellular delivery. Thereafter, we determine the contribution of each peptidase to QS signal production using systematic inducible overexpression in vivo, and confirm this activity operates through the physiological QS signalling pathway. Gene knockout of the QS-active peptidases identifies two enzymes, oligopeptidase B and metallocarboxypeptidase 1, that significantly reduce QS when ablated individually. Further, combinatorial gene knockout of both peptidases confirms their dominance in the generation of the QS signal, with peptidase release of oligopeptidase B mediated via an unconventional protein secretion pathway. This work identifies how the QS signal driving trypanosome virulence and transmission is generated in mammalian hosts.

Suggested Citation

  • Mabel Deladem Tettey & Federico Rojas & Keith R. Matthews, 2022. "Extracellular release of two peptidases dominates generation of the trypanosome quorum-sensing signal," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31057-1
    DOI: 10.1038/s41467-022-31057-1
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    References listed on IDEAS

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    1. Binny M. Mony & Paula MacGregor & Alasdair Ivens & Federico Rojas & Andrew Cowton & Julie Young & David Horn & Keith Matthews, 2014. "Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei," Nature, Nature, vol. 505(7485), pages 681-685, January.
    2. Samuel Dean & Rosa Marchetti & Kiaran Kirk & Keith R. Matthews, 2009. "A surface transporter family conveys the trypanosome differentiation signal," Nature, Nature, vol. 459(7244), pages 213-217, May.
    3. Emma M. Briggs & Federico Rojas & Richard McCulloch & Keith R. Matthews & Thomas D. Otto, 2021. "Single-cell transcriptomic analysis of bloodstream Trypanosoma brucei reconstructs cell cycle progression and developmental quorum sensing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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