Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | 107469 |
| Seiten (von - bis) | 3669-3696 |
| Seitenumfang | 28 |
| Fachzeitschrift | The EMBO journal |
| Jahrgang | 44 (2025) |
| Ausgabenummer | 13 |
| Frühes Online-Datum | 12 Mai 2025 |
| Publikationsstatus | Veröffentlicht - 1 Juli 2025 |
| Peer-Review-Status | Ja |
Externe IDs
| Scopus | 105004767857 |
|---|---|
| ORCID | /0000-0003-4017-6505/work/186620954 |