Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Medicine, The University of Chicago, Chicago, Illinois.
Endocrinology. 2019 Oct 1;160(10):2388-2394. doi: 10.1210/en.2019-00350.
N6-Methyladenosine (m6A) is the most common and abundant mRNA modification that involves regulating the RNA metabolism. However, the role of m6A in regulating the β-cell function is unclear. Methyltransferase-like 14 (METTL14) is a key component of the m6A methyltransferase complex. To define the role of m6A in regulating the β-cell function, we generated β-cell METTL14-specific knockout (βKO) mice by tamoxifen administration. Acute deletion of Mettl14 in β-cells results in glucose intolerance as a result of a reduction in insulin secretion in β-cells even though β-cell mass is increased, which is related to increased β-cell proliferation. To define the molecular mechanism, we performed RNA sequencing to detect the gene expression in βKO islets. The genes responsible for endoplasmic reticulum stress, such as Ire1α, were among the top upregulated genes. Both mRNA and protein levels of IRE1α and spliced X-box protein binding 1 (sXBP-1) were increased in βKO islets. The protein levels of proinsulin and insulin were decreased in βKO islets. These results suggest that acute METTL14 deficiency in β-cells induces glucose intolerance by increasing the IRE1α/sXBP-1 pathway.
N6-甲基腺苷（m6A）是最常见和丰富的 mRNA 修饰，涉及调节 RNA 代谢。然而，m6A 在调节β细胞功能中的作用尚不清楚。甲基转移酶样 14（METTL14）是 m6A 甲基转移酶复合物的关键组成部分。为了确定 m6A 在调节β细胞功能中的作用，我们通过给予他莫昔芬生成了β细胞 METTL14 特异性敲除（βKO）小鼠。β细胞中 Mettl14 的急性缺失导致葡萄糖耐量受损，这是由于β细胞胰岛素分泌减少，尽管β细胞质量增加，这与β细胞增殖增加有关。为了确定分子机制，我们进行了 RNA 测序以检测βKO 胰岛中的基因表达。内质网应激相关基因，如 Ire1α，是上调基因中的前几个。IRE1α 和剪接 X 盒蛋白结合 1（sXBP-1）的 mRNA 和蛋白水平在βKO 胰岛中均增加。βKO 胰岛中的胰岛素原和胰岛素蛋白水平降低。这些结果表明，β 细胞中急性 METTL14 缺乏通过增加 IRE1α/sXBP-1 通路诱导葡萄糖耐量受损。
