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). Mammalians and C. elegans intriguingly possess more than one paralog of miRNA-specific Argonautes and the dynamic between them remains unclear. Here, using C. elegans as a model system, we report dipeptidyl peptidase DPF-3 as a new interactor of miRNA-specific Argonautes ALG-1 and ALG-2. Knockout of dpf-3 rescues miRNA-related defects observed in alg-1 null animals and allows ALG-2 to better compensate for the lack of its paralog through higher expression and activity. While DPF-3 can cleave a N-terminal dipeptide of ALG-2 in vitro, we show that it is likely not the molecular mechanism used by DPF-3 to regulate ALG-2. This study uncovers the importance of a dipeptidyl peptidase in the miRNA pathway and provide insights in miRNA-specific Argonautes regulation dynamics in animals. Overall design: We compared the microRNA expression profile of young C. elegans adult animals of WT, dpf-3(xe68), alg-1(gk214) and alg-1(gk214);dpf-3(xe68) genetic background.