| First Author | Blandino-Rosano M | Year | 2022 |
| Journal | J Biol Chem | Volume | 298 |
| Issue | 3 | Pages | 101592 |
| PubMed ID | 35041827 | Mgi Jnum | J:329543 |
| Mgi Id | MGI:6886931 | Doi | 10.1016/j.jbc.2022.101592 |
| Citation | Blandino-Rosano M, et al. (2022) Trimethylguanosine synthase 1 is a novel regulator of pancreatic beta-cell mass and function. J Biol Chem 298(3):101592 |
| abstractText | Type 2 diabetes is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in beta-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs and that is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in beta-cells and glucose homeostasis had not been explored. Here, we show that TGS1 is upregulated by insulin and upregulated in islets of Langerhans from mice exposed to a high-fat diet and in human beta-cells from type 2 diabetes donors. Using mice with conditional (betaTGS1KO) and inducible (MIP-Cre(ERT)-TGS1KO) TGS1 deletion, we determined that TGS1 regulates beta-cell mass and function. Using unbiased approaches, we identified a link between TGS1 and endoplasmic reticulum stress and cell cycle arrest, as well as and how TGS1 regulates beta-cell apoptosis. We also found that deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2alpha, in addition to promoting several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating beta-cell mass and function. We propose that these observations can be used as a stepping-stone for the design of novel strategies focused on TGS1 as a therapeutic target for the treatment of diabetes. |
