️ Episode 137: Rethinking RNA-binding proteins: Riboregulation challenges prevailing views

In this episode of PaperCast Base by Base, we explore how a sweeping expansion of the RNA-binding proteome has reframed long‑held assumptions about RNA–protein interactions, spotlighting ‘non‑canonical’ RBPs and the emerging concept of riboregulation—RNA directly regulating protein function.

Study Highlights:
The authors synthesize discovery platforms that tripled the number of candidate RBPs, including UV crosslinking–based interactome capture (RIC/eRIC), silica‑based workflows (TRAPP/2C), and organic‑phase methods (OOPS/XRNAX), together with mass spectrometry to map RNA‑binding regions across the proteome. They show that intrinsically disordered regions and classical metabolite‑binding folds such as Rossmann domains frequently mediate RNA contacts, helping explain why many metabolic enzymes and signaling proteins appear in RBP datasets. Mechanistic case studies reveal RNA acting as a regulator of protein complexes and enzyme activity, exemplified by vtRNA1‑1 control of p62 oligomerization, SHMT1 inhibition by the SHMT2 5′UTR, ENO1 crowd‑control by UTR ligands, and circACC1 scaffolding of AMPK. The review outlines validation workflows and open questions to separate functional riboregulation from chance binding and artifacts, emphasizing orthogonal assays, target identification, and structure‑guided mutants.

Conclusion:
Together, these insights argue that riboregulation is likely widespread and clinically relevant, opening new routes to interrogate cell biology and to design therapeutic strategies that target RNA–protein interfaces.

Reference:
Hentze, M. W., Sommerkamp, P., Ravi, V., & Gebauer, F. (2025). Rethinking RNA-binding proteins: Riboregulation challenges prevailing views. Cell, 188, 4811–4822.

https://doi.org/10.1016/j.cell.2025.06.021

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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