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Dipeptidyl peptidase DPF-3 is a gatekeeper of microRNA Argonaute compensation in animals

Author

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  • Louis-Mathieu Harvey

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • Pierre-Marc Frédérick

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • Rajani Kanth Gudipati

    (Adam Mickiewicz University)

  • Pascale Michaud

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • François Houle

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • Daniel Young

    (University of Calgary
    University of Calgary)

  • Catherine Desbiens

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • Shanna Ladouceur

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

  • Antoine Dufour

    (University of Calgary
    University of Calgary)

  • Helge Großhans

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Martin J. Simard

    (CHU de Québec – Université Laval Research Center
    Université Laval Cancer Research Centre)

Abstract

MicroRNAs (miRNAs) are essential regulators involved in multiple biological processes. To achieve their gene repression function, they are loaded in miRNA-specific Argonautes to form the miRNA-induced silencing complex (miRISC). Mammals and C. elegans possess more than one paralog of miRNA-specific Argonautes, but the dynamic between them remains unclear. Here, we report the conserved dipeptidyl peptidase DPF-3 as an interactor of the miRNA-specific Argonaute ALG-1 in C. elegans. Knockout of dpf-3 increases ALG-2 levels and miRISC formation in alg-1 loss-of-function animals, thereby compensating for ALG-1 loss and rescuing miRNA-related defects observed. DPF-3 can cleave an ALG-2 N-terminal peptide in vitro but does not appear to rely on this catalytic activity to regulate ALG-2 in vivo. This study uncovers the importance of DPF-3 in the miRNA pathway and provides insights into how multiple miRNA Argonautes contribute to achieving proper miRNA-mediated gene regulation in animals.

Suggested Citation

  • Louis-Mathieu Harvey & Pierre-Marc Frédérick & Rajani Kanth Gudipati & Pascale Michaud & François Houle & Daniel Young & Catherine Desbiens & Shanna Ladouceur & Antoine Dufour & Helge Großhans & Marti, 2025. "Dipeptidyl peptidase DPF-3 is a gatekeeper of microRNA Argonaute compensation in animals," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58141-6
    DOI: 10.1038/s41467-025-58141-6
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    1. L. Robert Hollingsworth & Humayun Sharif & Andrew R. Griswold & Pietro Fontana & Julian Mintseris & Kevin B. Dagbay & Joao A. Paulo & Steven P. Gygi & Daniel A. Bachovchin & Hao Wu, 2021. "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation," Nature, Nature, vol. 592(7856), pages 778-783, April.
    2. Brenda J. Reinhart & Frank J. Slack & Michael Basson & Amy E. Pasquinelli & Jill C. Bettinger & Ann E. Rougvie & H. Robert Horvitz & Gary Ruvkun, 2000. "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans," Nature, Nature, vol. 403(6772), pages 901-906, February.
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