2. Academic Validation
  3. Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells

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

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. michele.solimena@tu-dresden.de.
  • 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. michele.solimena@tu-dresden.de.
  • 12 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. michele.solimena@tu-dresden.de.
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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