Molecular ’hub’ regulates gene-silencing proteins

A protein called GW182/TNRC6 acts as a hub to integrate the activities of differ
A protein called GW182/TNRC6 acts as a hub to integrate the activities of different protein complexes involved in RNA silencing.

To keep their vital functions in balance, many organisms use small snippets of RNA to ’silence’ messenger RNAs that code for certain proteins. New research from FMI scientists revealed a molecular hub that integrates the activities of different protein complexes involved in such RNA silencing. The findings provide insights into a key mechanism that helps to coordinate cellular functions.

In many plants and animals, small RNAs called miRNAs identify messenger RNAs that must be silenced by two proteins called Argonaute and GW182/TNRC6. Together, the two proteins and the miRNA form something called an RNA-induced silencing complex.

Researchers in the Grosshans lab and their collaborators at the University of Freiburg’s Medical Center and the Novartis Institutes for BioMedical Research found that, when GW182/TNRC6 doesn’t latch onto Argonaute proteins, it hobnobs with other RNA-binding proteins. All these different proteins appear to compete to get ahold of GW182/TNRC6: reducing Argonaute levels boosts the activity of the other proteins, which instead are inhibited when Argonaute is around, the researchers found.

The results suggest that GW182/TNRC6 acts as a hub to integrate the activities of different RNA-binding proteins. The findings also indicate that treatments that inhibit the miRNA pathway may boost the activity of other gene-silencing proteins, the authors say.

The project was in part supported by the Swiss National Center of Competence in Research RNA & Disease.

Thomas Welte*, Alison Goulois, Michael B. Stadler, Daniel Hess, Charlotte Soneson, Anca Neagu, Chiara Azzi, Marlena J. Wisser, Jan Seebacher, Isabel Schmidt, David Estoppey, Florian Nigsch, John Reece-Hoyes, Dominic Hoepfner, and Helge Großhans* Convergence of multiple RNA-silencing pathways on GW182/TNRC6 Molecular Cell (2023) Advance online publication
*co-corresponding authors

About the first author

Thomas Welte was born in Freiburg im Breisgau and grew up at Lake Constance in Germany. He obtained an MD from the University of Freiburg, where he studied the integration of membrane proteins. He then specialized in Internal Medicine and carried out a postdoc in the Grosshans lab at the FMI from 2017 to 2019. Since 2019, Thomas is a visiting scientist in the Grosshans group and is currently specializing in Nephrology. His hobbies include hiking, climbing and photography.