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<p>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-AMPKα<sup>Thr172</sup> and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1<sup>+</sup>/2<sup>+</sup> condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1<sup>+</sup>/2<sup>+</sup> condensates, increases phospho-AMPKα<sup>Thr172</sup> levels and reduces those of phospho-mTOR<sup>Ser2448</sup>. 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<sup>+</sup>/2<sup>+</sup> condensates. G3BP1<sup>+</sup>/2<sup>+</sup>/Ins mRNA<sup>+</sup> condensates are also found in primary mouse and human β-cells. Hence, G3BP1<sup>+</sup>/2<sup>+</sup> condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of insulin mRNA in resting β-cells.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月12日

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  • Esteban Quezada,
  • Klaus-Peter Knoch,
  • Jovana Vasiljevic,
  • Annika Seiler,
  • Akshaye Pal,
  • Abishek Gunasekaran,
  • Carla Münster,
  • Daniela Friedland,
  • Eyke Schöniger,
  • Anke Sönmez,
  • Pascal Roch,
  • Carolin Wegbrod,
  • Katharina Ganß,
  • Nicole Kipke,
  • Simon Alberti,
  • Rita Nano,
  • Lorenzo Piemonti,
  • Daniela Aust,
  • Jürgen Weitz,
  • Marius Distler,
  • Michele Solimena

摘要

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.