Science Topics - 73

Functional Loss of Cdkal1, a Novel tRNA Modification Enzyme, Causes the Development of Type 2 Diabetes

Fan-Yan Wei*

Cdk5 regulatory associated protein 1-like 1 (Cdkal1) has been associated with an impaired insulin response and increased risk of type 2 diabetes (T2D), but its molecular function has not been characterized. We have identified that Cdkal1 is a mammalian methylthiotransferase that specifically biosynthesizes 2-methylthio-N⁶-threonylcarbamoyladenosine (ms²t⁶A) at A37 of tRNA^Lys(UUU) and that it is required for the accurate translation of AAA and AAG codons. To further investigate the physiological role of Cdkal1, we generated pancreatic b-cell-specific Cdkal1 knockout mice (Cdkal1 knockout mice). Cdkal1 knockout mice showed pancreatic islet hypertrophy, a decrease in insulin secretion and impaired blood glucose control. In Cdkal1-deficient -cells, misreading of Lys codon in proinsulin was observed, which results in decrease of proinsulin synthesis. Consequently, the pancreatic C-peptide level was significantly decreased in Cdkal1 knockout mice. Moreover, the expression of endoplasmic reticulum (ER) stress-related genes was upregulated in pancreatic b-cells, and abnormally structured ER was observed. Furthermore, Cdkal1 knockout mice rapidly developed severe glucose intolerance under high fat diet feeding condition. There was a global increase of ER stress response in b-cells of Cdkal1 knockout mice fed with a high fat diet. These findings suggest that the induced translation of proinsulin may require fully modified tRNA^Lys(UUU), potentially explaining the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles. These findings have been published in the Journal of Clinical Investigation (doi:10.1172/JCI58056).

Figure Legend

(A) The secondary structure of tRNA^Lys(UUU) is shown. (B) Cdkal1 catalyzes the conversion of N⁶-threonylcarbamoyladenosine (t⁶) to 2-methylthio-N⁶-threonylcarbamoyladenosine (ms²t⁶A) at A37 of tRNA^Lys(UUU). (C) Proposed working model for regulation of b-cell function by Cdkal1 is shown.

* Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan