Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

Kenichi Izumi, Keiichiro Mine, Yoshitaka Inoue, Miho Teshima, Shuichiro Ogawa, Yuji Kai, Toshinobu Kurafuji, Kanako Hirakawa, Daiki Miyakawa, Haruka Ikeda, Akari Inada, Manami Hara, Hisakata Yamada, Koichi Akashi, Yoshiyuki Niho, Keisuke Ina, Takashi Kobayashi, Yasunobu Yoshikai, Keizo Anzai, Teruo Yamashita, Hiroko Minagawa, Shuji Fujimoto, Hironori Kurisaki, Kazuya Shimoda, Hitoshi Katsuta and Seiho Nagafuchi ()
Additional contact information
Kenichi Izumi: Graduate School of Medical Sciences, Kyushu University
Keiichiro Mine: Graduate School of Medical Sciences, Kyushu University
Yoshitaka Inoue: Graduate School of Medical Sciences, Kyushu University
Miho Teshima: Graduate School of Medical Sciences, Kyushu University
Shuichiro Ogawa: Graduate School of Medical Sciences, Kyushu University
Yuji Kai: Graduate School of Medical Sciences, Kyushu University
Toshinobu Kurafuji: Graduate School of Medical Sciences, Kyushu University
Kanako Hirakawa: Graduate School of Medical Sciences, Kyushu University
Daiki Miyakawa: Graduate School of Medical Sciences, Kyushu University
Haruka Ikeda: Graduate School of Medical Sciences, Kyushu University
Akari Inada: Graduate School of Medical Sciences, Kyushu University
Manami Hara: University of Chicago
Hisakata Yamada: Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University
Koichi Akashi: Graduate School of Medical Sciences, Kyushu University
Yoshiyuki Niho: Graduate School of Medical Sciences, Kyushu University
Keisuke Ina: Faculty of Medicine, Oita University
Takashi Kobayashi: Faculty of Medicine, Oita University
Yasunobu Yoshikai: Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University
Keizo Anzai: Diabetes and Endocrinology, School of Medicine, Saga University
Teruo Yamashita: Aichi Prefectural Institute of Public Health
Hiroko Minagawa: Aichi Prefectural Institute of Public Health
Shuji Fujimoto: Graduate School of Medical Sciences, Kyushu University
Hironori Kurisaki: Graduate School of Medical Sciences, Kyushu University
Kazuya Shimoda: Faculty of Medicine, University of Miyazaki
Hitoshi Katsuta: Graduate School of Medical Sciences, Kyushu University
Seiho Nagafuchi: Graduate School of Medical Sciences, Kyushu University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7748

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