TY - JOUR
T1 - Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice
AU - Wei, Fan Yan
AU - Suzuki, Takeo
AU - Watanabe, Sayaka
AU - Kimura, Satoshi
AU - Kaitsuka, Taku
AU - Fujimura, Atsushi
AU - Matsui, Hideki
AU - Atta, Mohamed
AU - Michiue, Hiroyuki
AU - Fontecave, Marc
AU - Yamagata, Kazuya
AU - Suzuki, Tsutomu
AU - Tomizawa, Kazuhito
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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-N6- threonylcarbamoyladenosine (ms2t 6A) in tRNALys(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 tRNALys(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.
AB - 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-N6- threonylcarbamoyladenosine (ms2t 6A) in tRNALys(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 tRNALys(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.
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U2 - 10.1172/JCI58056
DO - 10.1172/JCI58056
M3 - Article
C2 - 21841312
AN - SCOPUS:80052375980
VL - 121
SP - 3598
EP - 3608
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 9
ER -