Welte, Thomas, Goulois, Alison, Neagu, Anca, Azzi, Chiara, Lübke, Marlena, Stadler, Michael, Hess, Daniel, Schmidt, Isabel, Estoppey, David, Nigsch, Florian, Reece-Hoyes, John, Hoepfner, Dominic and Grosshans, Helge (2023) Convergence of distinct RNA-silencing pathways on GW182/Tnrc6. Molecular Cell, 83 (14). pp. 2478-2492. ISSN https://doi.org/10.1016/j.molcel.2023.06.001

Abstract

The RNA-binding protein Trim71/Lin41 is a phylogenetically conserved developmental regulator that functions in mammalian stem cell reprogramming, brain development and cancer. Trim71 recognizes target mRNAs through hairpin motifs and silences them through molecular mechanisms that await identification. Using a genome-wide CRISPR-based screen, we find that the miRNA pathway attenuates Trim71 activity in mouse embryonic stem cells (mESCs). This interaction does not involve regulation of Trim71 levels, which are not limiting for Trim71 activity in mESCs. Instead, Trim71 competes with Argonaute (Ago) proteins for GW182/Tnrc6 proteins as shared silencing factors. We show that Trim71 and Ago2 recruit Tnrc6 both to unique and to shared target transcripts. Our results provide insight into the mechanism of action of Trim71 and identify an unexpected function of Tnrc6 outside the miRNA-induced silencing complex (miRISC). By functioning in distinct silencing pathways, Tnrc6s provide a means to integrate the activity of distinct silencing pathways through competition and, potentially, cooperation.

Item Type:	Article
Keywords:	TRIM71; LIN41; RNA-binding protein; stem cell; miRNA; AGO2; GW182; miRISC; TNRC6; post-transcriptional gene regulation
Date Deposited:	07 Oct 2023 00:45
Last Modified:	07 Oct 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47762