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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Esteban Quezada - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Klaus-Peter Knoch - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Jovana Vasiljevic - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Annika Seiler - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Akshaye Pal - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Abishek Gunasekaran - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Carla Münster - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Daniela Friedland - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich (Author)
  • Eyke Schöniger - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Anke Sönmez - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Pascal Roch - , German Center for Diabetes Research (DZD), Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich (Author)
  • Carolin Wegbrod - , German Center for Diabetes Research (DZD), Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich (Author)
  • Katharina Ganß - , German Center for Diabetes Research (DZD), Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich (Author)
  • Nicole Kipke - , German Center for Diabetes Research (DZD), Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich (Author)
  • Simon Alberti - , Chair of Cellular Biochemistry (Author)
  • Rita Nano - , Vita-Salute San Raffaele University, IRCCS Hospital San Raffaele - Milano (Author)
  • Lorenzo Piemonti - , Vita-Salute San Raffaele University, IRCCS Hospital San Raffaele - Milano (Author)
  • Daniela Aust - , Institute of Pathology (Author)
  • Jürgen Weitz - , Department of Visceral, Thoracic and Vascular Surgery, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)
  • Marius Distler - , Department of Visceral, Thoracic and Vascular Surgery, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD), University Hospital Carl Gustav Carus Dresden (Author)
  • Michele Solimena - , Molecular Diabetology, Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, German Center for Diabetes Research (DZD) (Author)

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.

Details

Original languageEnglish
Article number107469
Pages (from-to)3669-3696
Number of pages28
JournalThe EMBO journal
Volume44 (2025)
Issue number13
Early online date12 May 2025
Publication statusPublished - 1 Jul 2025
Peer-reviewedYes

External IDs

Scopus 105004767857
ORCID /0000-0003-4017-6505/work/186620954

Keywords

Sustainable Development Goals