Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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 language | English |
|---|---|
| Article number | 107469 |
| Pages (from-to) | 3669-3696 |
| Number of pages | 28 |
| Journal | The EMBO journal |
| Volume | 44 (2025) |
| Issue number | 13 |
| Early online date | 12 May 2025 |
| Publication status | Published - 1 Jul 2025 |
| Peer-reviewed | Yes |
External IDs
| Scopus | 105004767857 |
|---|---|
| ORCID | /0000-0003-4017-6505/work/186620954 |