Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Commun Biol. 2020 Aug 28;3(1):476. doi: 10.1038/s42003-020-01201-y.
Pancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4-NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.
胰岛β细胞负责响应血糖水平升高而产生和分泌胰岛素。β细胞功能缺陷会导致高血糖和糖尿病。在这里，我们发现 CCR4-NOT 去腺苷酸化复合物亚基 CNOT3 在糖尿病 db/db 小鼠的胰岛中失调，并且对于鼠β细胞成熟和特性是必需的。β细胞特异性敲除 Cnot3（Cnot3βKO）的小鼠表现出葡萄糖耐量受损、β细胞质量减少，并且逐渐发展为糖尿病。Cnot3βKO 胰岛显示出关键调节因子的表达减少β细胞成熟和功能。此外，它们还显示出祖细胞标志物、β细胞不允许的基因以及与改变的β细胞功能相关的基因增加。Cnot3βKO 胰岛表现出脱腺苷酸化改变和 mRNA 稳定性增加，部分解释了这些基因表达增加的原因。总之，这些数据表明 CNOT3 介导的 mRNA 脱腺苷酸化和衰减构成了以前未被怀疑的对于β细胞特性至关重要的转录后机制。
