In wild-type conditions, the Argonaute protein ALG-1 takes care of most miRNA-mediated functions with a small contribution by the Argonaute protein ALG-2. If ALG-1 is genetically ablated, the worm cells try to compensate the loss by transcribing more ALG-2 pre-mRNA. Howevert, these pre-mRNAs are not processed to mature mRNAs because of the inhibitory effect that the peptidase DPF-3 has on their processing. This lack of ALG-1 leads to sick and dead animals. If however, DPF-3 function is ablated as well, enough mature mRNAs of ALG-2 are processed that enough ALG-2 proteins can compensate for the loss of ALG-1 restoring the animals' fitness. Interstingly, in the wild-type worms DPF-3 directly interacts with ALG-1. These findings were made by the Simard (Université Laval Research Center, Québec, Canada) lab in collaboration with the Dufour (University of Calgary, Calgary, Canada), Gudipati (Adam Mickiewicz University, Poznan, Poland) and Grosshans (FMI Basel, Switzerland) labs and published in the Nature Communications article "Dipeptidyl peptidase DPF-3 is a gatekeeper of microRNA Argonaute compensation in animals".
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.
Read the Publication in Nature Communications (Open Access)
Abstract, figure and title from Harvey et al (2025) Nature Communications published under a CC BY-NC-ND 4.0 license.