title: Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.
abstract: Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.
authors: 1] Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan [2] Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan [3] Department of Hepatology, Diabetes and Endocrinology, School of Medicine, Saga University, Saga 849-8501, Japan.
authors: Kenichi
authors: K
authors: Izumi
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Keiichiro
authors: K
authors: Mine
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Yoshitaka
authors: Y
authors: Inoue
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Miho
authors: M
authors: Teshima
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Shuichiro
authors: S
authors: Ogawa
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Yuji
authors: Y
authors: Kai
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Toshinobu
authors: T
authors: Kurafuji
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Kanako
authors: K
authors: Hirakawa
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Daiki
authors: D
authors: Miyakawa
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Haruka
authors: H
authors: Ikeda
authors: Department of Diabetes and Genes, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Akari
authors: A
authors: Inada
authors: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors: Manami
authors: M
authors: Hara
authors: Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors: Hisakata
authors: H
authors: Yamada
authors: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Koichi
authors: K
authors: Akashi
authors: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Yoshiyuki
authors: Y
authors: Niho
authors: Department of Molecular Anatomy, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
authors: Keisuke
authors: K
authors: Ina
authors: Department of Infectious Diseases Control, Faculty of Medicine, Oita University, Oita 879-5593, Japan.
authors: Takashi
authors: T
authors: Kobayashi
authors: Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors: Yasunobu
authors: Y
authors: Yoshikai
authors: Department of Hepatology, Diabetes and Endocrinology, School of Medicine, Saga University, Saga 849-8501, Japan.
authors: Keizo
authors: K
authors: Anzai
authors: Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health, 7-6 Nagare, Tsujimachi, Kita-ku, Nagoya, Aichi 462-8576, Japan.
authors: Teruo
authors: T
authors: Yamashita
authors: Department of Microbiology and Medical Zoology, Aichi Prefectural Institute of Public Health, 7-6 Nagare, Tsujimachi, Kita-ku, Nagoya, Aichi 462-8576, Japan.
authors: Hiroko
authors: H
authors: Minagawa
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Shuji
authors: S
authors: Fujimoto
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Hironori
authors: H
authors: Kurisaki
authors: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
authors: Kazuya
authors: K
authors: Shimoda
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Hitoshi
authors: H
authors: Katsuta
authors: Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Seiho
authors: 0000000287908358
authors: S
authors: Nagafuchi
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000821:virology; D004686:Encephalomyocarditis virus; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007370:Interferon Type I; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism*; D053634:TYK2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D012333:RNA, Messenger; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse