Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice

Abstract

The worldwide prevalence of type 2 diabetes (T2D), which is caused by a combination of environmental and genetic factors, is increasing. With regard to genetic factors, variations in the gene encoding Cdk5 regulatory associated protein 1-like 1 (Cdkal1) have been associated with an impaired insulin response and increased risk of T2D across different ethnic populations, but the molecular function of this protein has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N 6 -threonylcarbamoyladenosine (ms 2 t 6 A) in tRNA Lys (UUU) and that it is required for the accurate translation of AAA and AAG codons. Mice with pancreatic β cell-specific KO of Cdkal1 (referred to herein as β cell KO mice) showed pancreatic islet hypertrophy, a decrease in insulin secretion, and impaired blood glucose control. In Cdkal1-deficient β cells, misreading of Lys codon in proinsulin occurred, resulting in a reduction of glucosestimulated proinsulin synthesis. Moreover, expression of ER stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Further, the β cell KO mice were hypersensitive to high fat diet-induced ER stress. These findings suggest that glucose-stimulated translation of proinsulin may require fully modified tRNA Lys (UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case–control study in Han Chinese

“…Beta cellspecific CDKAL1 knockout mice models suggested that functional loss of CDKAL1 affects the accuracy of protein translation, causing the synthesis of abnormal insulin, which triggers estrogen receptor stress in beta cells. 30,31 The significant association between the SNP rs9472138 (about 73 kb to the transcription start site of VEGFA) and T2D was firstly replicated among Chinese population. Zeggini et al first reported in Caucasian that rs9472138 was associated with T2D in GWAS scan and the first stage validation, but achieved a borderline significant association (P¼0.095) in the second stage validation.…”

Functional loss of Cdkal1, a novel tRNA modification enzyme, causes the development of type 2 diabetes [Review]

“…As Cdk5 regulates insulin secretion [17,18], it is postulated that Cdkal1 may regulate insulin secretion through the regulation of Cdk5 activity. However, Cdkal1 has no ability to interact with Cdk5 activators and no effect on Cdk5 activity [19,20]. The primary structure of Cdkal1 has features of the methylthiotransferase (MTTase) family, a subclass of the large radical AdoMet enzyme superfamily [21].…”

“…Interestingly, the C-terminal hydrophobic domain exists only in Cdkal1 ( Fig. 2A) and the domain contributes to the localization on the endoplasmic reticulum (ER) [20].…”

“…These results suggest that pancreatic β-cells may be susceptible to the risk variants in the cdkal1 gene. To investigate the physiological functions of Cdkal1 in pancreatic β-cells, β-cell-specific Cdkal1-deficient mice (KO mice) were generated [20]. KO mice showed normal development compared with their littermate controls (Flox) [20].…”

“…To investigate the physiological functions of Cdkal1 in pancreatic β-cells, β-cell-specific Cdkal1-deficient mice (KO mice) were generated [20]. KO mice showed normal development compared with their littermate controls (Flox) [20]. However, KO mice exhibited glucose intolerance, whereas the peripheral insulin sensitivity was normal.…”