Characterization of Cdkal1, a novel type 2 diabetes risk gene

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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.