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Characterization of Cdkal1, a novel type 2 diabetes risk gene

新型 2 型糖尿病风险基因 Cdkal1 的表征

基本信息

批准号：
22790214
负责人：
WEI Fanyan
金额：
$ 2.5万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790214/
关键词：
病態生理糖尿病 tRNA インリン 2型糖尿病インスリン β細胞

项目摘要

Genetic variations in cdkal1(Cdk5 regulatory subunit associated protein 1-like 1) have been identified as a risk for type 2 diabetes. Despite the accumulating clinical evidence, the molecular characterization of Cdkal1 is completely unknown. To investigate the physiological role of Cdkal1, pancreatic b-cell-specific Cdkal1 knockout(Cdkal1 KO) mice were generated. Cdkal1 KO mice showed glucose intolerance and impaired insulin secretion. We have identified that Cdkal1 is a mammalian methylthiotranferase, which specifically modifies tRNA^<Lys>(UUU) at position 37 by catalyzing the biosynthesis of N6-threonylcabamoyladenosine(t6A) to 2-methylthio-N6-threonylcabamoyladenosine(ms2t6A) in both bacteria and mammalian cells. Modification of tRNA^<Lys>(UUU) by Cdkal1 is critical for the accurate decoding of Lys codon. In Cdkal1 KO b-cells, deficiency of modification in tRNA^<Lys>(UUU) caused mistranslation of proinsulin and thus triggered endoplasmic reticulum(ER) stress response. Furthermore, Cdkal1 KO mice fed with a high fat diet developed severe glucose intolerance and ER stress response. From these results, we concluded that modification of tRNA by Cdkal1 in b-cells is critical to maintaining translation fidelity, which contributes to the homeostasis of b-cells.

cdkal 1（Cdk 5调节亚基相关蛋白1样1）的遗传变异已被确定为2型糖尿病的风险。尽管积累的临床证据，Cdkal 1的分子特征是完全未知的。为了研究Cdkal 1的生理作用，产生胰腺b细胞特异性Cdkal 1敲除（Cdkal 1 KO）小鼠。Cdkal 1基因敲除小鼠表现出葡萄糖耐受不良和胰岛素分泌受损。我们已经确定Cdkal 1是哺乳动物甲硫基转移酶，其<Lys>通过在细菌和哺乳动物细胞中催化N6-苏氨酰氨甲酰腺苷（t6 A）生物合成为2-甲硫基-N6-苏氨酰氨甲酰腺苷（ms 2 t6 A）来特异性地修饰37位的tRNA^（UUU）。Cdkal 1对tRNA^<Lys>（UUU）的修饰是正确解码Lys密码子的关键。在Cdkal 1 KO b细胞中，tRNA^（UUU）修饰的缺陷<Lys>导致胰岛素原的错误翻译，从而触发内质网（ER）应激反应。此外，Cdkal 1基因敲除小鼠喂养高脂肪饮食发展严重的葡萄糖耐受不良和ER应激反应。从这些结果中，我们得出结论，在b细胞中由Cdkal 1修饰tRNA对于维持翻译保真度至关重要，这有助于b细胞的稳态。