137: Rethinking RNA-binding proteins: riboregulation beyond the classics

Hentze MW et al., Cell - A review that examines the expansion of the RNA-binding proteome, evaluates evidence for many non-canonical RBPs, and highlights riboregulation as an emerging mechanism by which RNA controls protein function, complexes, and metabolism. Key terms: RNA-binding proteins, non-canonical RBPs, riboregulation, intrinsically disordered regions, RNA interactome.

Study Highlights:
Large-scale UV crosslinking and proteomic approaches have dramatically expanded the catalogue of RNA-binding proteins to include many non-canonical, well-studied proteins that lack classical RNA-binding domains. Mapping efforts show that IDRs and nucleotide cofactor-binding folds frequently mediate these interactions, and validated examples reveal RNA can regulate protein-protein interactions, enzymatic activity, complex assembly, and transmembrane import. Representative cases include IRP1, GAPDH, ENO1, SHMT1, p62/vtRNA1-1, and lncRNA/circRNA regulators of metabolic enzymes and signaling complexes. The authors emphasize the need for orthogonal validation, high-resolution structures, and in vivo functional studies to distinguish biologically relevant riboregulation from methodological artifacts.

Conclusion:
Riboregulation extends RNA function beyond classical targets: many non-canonical RBPs engage RNA via IDRs or metabolic folds and RNA can directly modulate protein activity, interactions, and assemblies; rigorous validation and structural work are essential to define mechanism and relevance for physiology and disease.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Rethinking RNA-binding proteins: Riboregulation challenges prevailing views

First author:
Hentze MW

Journal:
Cell

DOI:
10.1016/j.cell.2025.06.021

Reference:
Hentze MW, Sommerkamp P, Ravi V, Gebauer F. Rethinking RNA-binding proteins: Riboregulation challenges prevailing views. Cell. 2025;188:4811-4827. 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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Episode link: https://basebybase.com/episodes/rethinking-rna-binding-proteins-riboregulation-challenges-prevailing-views

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the narration's depiction of riboregulation concepts, non-canonical RBPs, validation methods (UV crosslinking, RIC/eRIC, OOPS/PTex, EU labeling, PLA, NMR), IDRs and Rossmann-fold binding surfaces, and functional examples (P62/vtRNA1-1, SHMT1, ENO1, metabolon formation with GlycoLINC, ATP5A1 import), plus virolo
- transcript topics: Riboregulation concept and paradigm shift; Non-canonical RNA-binding proteins (RBPs) and loss of classical RBDs; Validation technologies for RNA–protein interactions (UV crosslinking, RIC/eRIC, OOPS/PTex, EU labeling, PLA, NMR); IDRs as RNA-binding surfaces and Rossmann-fold cofactor pockets; Functional mechanisms: allostery, oligomerization, metabolon scaffolding; Specific riboregulation examples: P62/vtRNA1-1, SHMT1, ENO1,...