Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells

  • EMBO J. 2025 Jul;44(13):3669-3696. doi: 10.1038/s44318-025-00448-7.
Esteban Quezada  1  2  3 ,  Klaus-Peter Knoch  1  2  3 ,  Jovana Vasiljevic  1  2  3 ,  Annika Seiler  1  2  3 ,  Akshaye Pal  4 ,  Abishek Gunasekaran  1  2  3 ,  Carla Münster  1  2  3 ,  Daniela Friedland  1  2  3 ,  Eyke Schöniger  1  2  3 ,  Anke Sönmez  1  2  3 ,  Pascal Roch  1  2  3 ,  Carolin Wegbrod  1  2  3 ,  Katharina Ganß  1  2  3 ,  Nicole Kipke  1  2  3 ,  Simon Alberti  5 ,  Rita Nano  6  7 ,  Lorenzo Piemonti  6  7 ,  Daniela Aust  8 ,  Jürgen Weitz  2  3  9 ,  Marius Distler  2  3  9 ,  Michele Solimena  10  11  12
Affiliations
  • 1. Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
  • 2. Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
  • 3. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
  • 4. Max Planck Institute of Molecular Cell Biology and Genetics, 01307, Dresden, Germany.
  • 5. Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering, TU Dresden, Dresden, Germany.
  • 6. Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 7. Università Vita-Salute San Raffaele, Milan, Italy.
  • 8. Department of Pathology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden Germany, TU Dresden, Dresden, Germany.
  • 9. Department of Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
  • 10. Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany. [email protected].
  • 11. Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany. [email protected].
  • 12. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. [email protected].
PMID: 40355555 DOI: 10.1038/s44318-025-00448-7
Abstract

Upregulation of Insulin mRNA translation upon hyperglycemia in pancreatic islet β-cells involves several RNA-binding proteins. Here, we found that G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes, binds to Insulin mRNA in glucose concentration-dependent manner. We show in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels that G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b, phospho-AMPKαThr172 and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1+/2+ condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1+/2+ condensates, increases phospho-AMPKαThr172 levels and reduces those of phospho-mTORSer2448. G3BP1 or G3BP2 depletion precludes condensate assembly. KO of G3BP1 decreases Ins1/2 mRNA abundance and translation as well as proinsulin levels, and impaires glucose-stimulated Insulin secretion. Further, other Insulin secretagogues such as exendin-4 and palmitate, but not high KCl, prompts the dissolution of G3BP1+/2+ condensates. G3BP1+/2+/Ins mRNA+ condensates are also found in primary mouse and human β-cells. Hence, G3BP1+/2+ condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of Insulin mRNA in resting β-cells.

Keywords
Diabetes; Insulin; Islet; Stress Granules; Translation.
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