m6A 阅读器 IMP2/IGF2BP2 通过增强 PDX1 表达促进胰腺 β 细胞增殖和胰岛素分泌。
RNA m6A reader IMP2/IGF2BP2 promotes pancreatic β-cell proliferation and insulin secretion by enhancing PDX1 expression.
机构信息
Department of Molecular Biology and Diabetes Unit of the Medical Services, Massachusetts General Hospital, Boston, 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
出版信息
Mol Metab. 2021 Jun;48:101209. doi: 10.1016/j.molmet.2021.101209. Epub 2021 Mar 9.
BACKGROUND
Type 2 diabetes (T2D) is a common metabolic disease. Variants in human IGF2 mRNA binding protein 2 (IMP2/IGF2BP2) are associated with increased risk of T2D. IMP2 contributes to T2D susceptibility primarily through effects on insulin secretion. However, the underlying mechanism is not known.
METHODS
To understand the role of IMP2 in insulin secretion and T2D pathophysiology, we generated Imp2 pancreatic β-cell specific knockout mice (βIMP2KO) by recombining the Imp2 allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of βIMP2KO mice and assessed their β-cell functions.
RESULTS
The deletion of IMP2 in pancreatic β-cells leads to reduced compensatory β-cell proliferation and function. Mechanically, IMP2 directly binds to Pdx1 mRNA and stimulates its translation in an m6A dependent manner. Moreover, IMP2 orchestrates IGF2-AKT-GSK3β-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-βH1 cells, the over-expression of IMP2 is capable to enhance cell proliferation, PDX1 protein level and insulin secretion.
CONCLUSION
Our work therefore reveals IMP2 as a critical regulator of pancreatic β-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology.
背景
2 型糖尿病（T2D）是一种常见的代谢疾病。人类 IGF2mRNA 结合蛋白 2（IMP2/IGF2BP2）的变异与 T2D 风险增加有关。IMP2 通过对胰岛素分泌的影响主要导致 T2D 易感性。然而，其潜在机制尚不清楚。
方法
为了了解 IMP2 在胰岛素分泌和 T2D 病理生理学中的作用，我们通过重组 Imp2 等位基因与大鼠胰岛素 2 启动子驱动的 Cre 重组酶，在胰腺β细胞中生成 Imp2 特异性敲除小鼠（βIMP2KO）。我们进一步表征了βIMP2KO 小鼠的代谢表型，并评估了它们的β细胞功能。
结果
胰腺β细胞中 IMP2 的缺失导致代偿性β细胞增殖和功能减少。机制上，IMP2 直接结合 Pdx1mRNA 并以 m6A 依赖的方式刺激其翻译。此外，IMP2 协调 IGF2-AKT-GSK3β-PDX1 信号通路以稳定 PDX1 多肽。在人 EndoC-βH1 细胞中，IMP2 的过表达能够增强细胞增殖、PDX1 蛋白水平和胰岛素分泌。
结论
因此，我们的工作揭示了 IMP2 是胰腺β细胞增殖和功能的关键调节因子；强调了转录后基因表达在 T2D 发病机制中的重要性。
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