Convergence of multiple RNA-silencing pathways on GW182/TNRC6

The RNA-binding protein TRIM71/LIN-41 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. Here, we uncover that TRIM71 represses its targets through RNA-supported interaction with TNRC6/ GW182, a core component of the miRNA-induced silencing complex (miRISC). We demonstrate that AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific sets of transcripts to silence them. As cellular TNRC6 levels are limiting, competition occurs among the silencing pathways, such that the loss of AGO proteins or of AGO binding to TNRC6 enhances the activities of the other pathways. We conclude that a miRNA-like silencing activity is shared among different mRNA silencing pathways and that the use of TNRC6 as a central hub provides a means to integrate their activities.

Automated summary

The RNA-binding protein TRIM71/LIN-41, a highly conserved developmental regulator, plays important roles in mammalian stem cell reprogramming, brain development, and cancer. It has been discovered that TRIM71 represses its target mRNAs by interacting with TNRC6/GW182, a key component of the miRNA-induced silencing complex. AGO2, TRIM71, and UPF1 recruit TNRC6 to specific transcripts and silence them. Competition occurs among different silencing pathways due to limited cellular TNRC6 levels, and loss of AGO proteins or AGO binding to TNRC6 enhances the activities of other pathways. Therefore, a miRNA-like silencing activity is shared among different mRNA silencing pathways through the use of TNRC6 as a central hub.