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

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 a new interactor of the miRNA-specific Argonautes ALG-1 and ALG-2 in C. elegans. Knockout of dpf-3 increases ALG-2 levels and miRISC formation in alg-1 null 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 on how multiple miRNA Argonautes contribute to achieve proper miRNA-mediated gene regulation in animals.