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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 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.

INSTRUMENT(S):

ORGANISM(S): Caenorhabditis Elegans

TISSUE(S): Whole Body

SUBMITTER: Luiz Gustavo de Almeida

LAB HEAD: Antoine Dufour

PROVIDER: PXD055867 | Pride | 2025-03-06

REPOSITORIES: Pride

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			Action	DRS
	Jan_10_2022_Louis_DPF_TAILS.zip	Other
	S13962_813_Louis_DPF_PreTails_2_221217.raw	Raw
	S13963_814_Louis_DPF_PreTails_3_221217.raw	Raw
	S13964_815_Louis_DPF_Tails_1_221217.raw	Raw
	S13965_816_Louis_DPF_Tails_2_221217.raw	Raw

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

Project description: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.

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