Post-transcriptional regulation of insulin mRNA storage by G3BP1/2+ condensates in beta cells

• Published in: bioRxiv
• Main Authors: Quezada, Esteban, Vasiljevic, Jovana, Pal, Akshaye, Münster, Carla, Friedland, Daniela, Schöniger, Eyke, Sönmez, Anke, Seiler, Annika, Roch, Pascal, Wegbrod, Carolin, Ganß, Katharina, Knoch, Klaus-Peter, Kipke, Nicole, Alberti, Simon, Nano, Rita, Piemonti, Lorenzo, Aust, Daniela, Weitz, Jürgen, Distler, Marius, Solimena, Michele
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Laboratory 25.05.2024
• Edition: 1.1
• Subjects: Molecular Biology; stress granules; translation; insulin; islet; diabetes Running title: G3BP1 condensate in beta cells; G3BP1
• ISSN: 2692-8205
• DOI: 10.1101/2024.05.25.595863

Hyperglycemia upregulates insulin translation in pancreatic beta cells. Several RNA- binding proteins involved in this process have been identified, including G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes. We show that in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b and Ins1/2 mRNA. Upon glucose stimulation, the condensates dissolve and G3BP1/2, eIF3b, and insulin mRNAs redistribute throughout the cytosol. Intriguingly, G3BP1+ condensates in MIN6-K8 cells differ from sodium arsenate-induced stress granules in regards to eIF2α and AMPKα phosphorylation. Knockout of G3BP1 or G3BP2 prevented condensate assembly, but only G3BP1 deletion decreased the levels of Ins1/2 mRNA and proinsulin and impaired polysome formation. Like glucose, other insulin secretagogues such as Exendin-4 and palmitate, but not high KCl, prompted the dissolution of G3BP1+ condensates. G3BP1+/Ins mRNA+ condensates were also present in mouse and human beta cells from normoglycemic donors. Hence, G3BP1+ condensates represent a glucose-regulated compartment for the physiological storage and protection of insulin mRNA in resting beta cells.