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

Louis-Mathieu Harvey, Pierre-Marc Frédérick, Rajani Kanth Gudipati, Pascale Michaud, François Houle, Daniel Young, Catherine Desbiens, Shanna Ladouceur, Antoine Dufour, Helge Großhans and Martin J. Simard ()
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Louis-Mathieu Harvey: CHU de Québec – Université Laval Research Center
Pierre-Marc Frédérick: CHU de Québec – Université Laval Research Center
Rajani Kanth Gudipati: Adam Mickiewicz University
Pascale Michaud: CHU de Québec – Université Laval Research Center
François Houle: CHU de Québec – Université Laval Research Center
Daniel Young: University of Calgary
Catherine Desbiens: CHU de Québec – Université Laval Research Center
Shanna Ladouceur: CHU de Québec – Université Laval Research Center
Antoine Dufour: University of Calgary
Helge Großhans: Friedrich Miescher Institute for Biomedical Research
Martin J. Simard: CHU de Québec – Université Laval Research Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58141-6

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