| First Author | Jo S | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 35 | Pages | 13040-13050 |
| PubMed ID | 31300553 | Mgi Jnum | J:281152 |
| Mgi Id | MGI:6369298 | Doi | 10.1074/jbc.RA119.008670 |
| Citation | Jo S, et al. (2019) eIF4G1 and carboxypeptidase E axis dysregulation in O-GlcNAc transferase-deficient pancreatic beta-cells contributes to hyperproinsulinemia in mice. J Biol Chem 294(35):13040-13050 |
| abstractText | An early hallmark of type 2 diabetes is a failure of proinsulin-to-insulin processing in pancreatic beta-cells, resulting in hyperproinsulinemia. Proinsulin processing is quite sensitive to nutrient flux, and beta-cell-specific deletion of the nutrient-sensing protein modifier OGlcNAc transferase (betaOGTKO) causes beta-cell failure and diabetes, including early development of hyperproinsulinemia. The mechanisms underlying this latter defect are unknown. Here, using several approaches, including site-directed mutagenesis, Click O-GlcNAc labeling, immunoblotting, and immunofluorescence and EM imaging, we provide the first evidence for a relationship between the O-GlcNAcylation of eukaryotic translation initiation factor 4gamma1 (eIF4G1) and carboxypeptidase E (CPE)-dependent proinsulin processing in betaOGTKO mice. We first established that betaOGTKO hyperproinsulinemia is independent of age, sex, glucose levels, and endoplasmic reticulum-CCAAT enhancer-binding protein homologous protein (CHOP)-mediated stress status. Of note, OGT loss was associated with a reduction in beta-cell-resident CPE, and genetic reconstitution of CPE in betaOGTKO islets rescued the dysfunctional proinsulin-to-insulin ratio. We show that although CPE is not directly OGlcNAc modified in islets, overexpression of the suspected OGT target eIF4G1, previously shown to regulate CPE translation in beta-cells, increases islet CPE levels, and fully reverses betaOGTKO islet-induced hyperproinsulinemia. Furthermore, our results reveal that OGT O-GlcNAc-modifies eIF4G1 at Ser-61 and that this modification is critical for eIF4G1 protein stability. Together, these results indicate a direct link between nutrient-sensitive OGT and insulin processing, underscoring the importance of post-translational O-GlcNAc modification in general cell physiology. |
