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 YamashitaHiroko Minagawa, Shuji Fujimoto, Hironori Kurisaki, Kazuya Shimoda, Hitoshi Katsuta, Seiho Nagafuchi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number6748
JournalNature communications
Volume6
DOIs
Publication statusPublished - Apr 13 2015

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TYK2 Kinase
gene expression
tyrosine
viruses
Medical problems
mutations
Viruses
Gene expression
magnetic permeability
Gene Expression
Mutation
cells
genes
mice
Genes
interferon
Interferon Type I
Interferons
Antiviral Agents
dosage

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. / Izumi, Kenichi; Mine, Keiichiro; Inoue, Yoshitaka; Teshima, Miho; Ogawa, Shuichiro; Kai, Yuji; Kurafuji, Toshinobu; Hirakawa, Kanako; Miyakawa, Daiki; Ikeda, Haruka; Inada, Akari; Hara, Manami; Yamada, Hisakata; Akashi, Koichi; Niho, Yoshiyuki; Ina, Keisuke; Kobayashi, Takashi; Yoshikai, Yasunobu; Anzai, Keizo; Yamashita, Teruo; Minagawa, Hiroko; Fujimoto, Shuji; Kurisaki, Hironori; Shimoda, Kazuya; Katsuta, Hitoshi; Nagafuchi, Seiho.

In: Nature communications, Vol. 6, 6748, 13.04.2015.

Research output: Contribution to journalArticle

Izumi, K, Mine, K, Inoue, Y, Teshima, M, Ogawa, S, Kai, Y, Kurafuji, T, Hirakawa, K, Miyakawa, D, Ikeda, H, Inada, A, Hara, M, Yamada, H, Akashi, K, Niho, Y, Ina, K, Kobayashi, T, Yoshikai, Y, Anzai, K, Yamashita, T, Minagawa, H, Fujimoto, S, Kurisaki, H, Shimoda, K, Katsuta, H & Nagafuchi, S 2015, 'Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes', Nature communications, vol. 6, 6748. https://doi.org/10.1038/ncomms7748
Izumi, Kenichi ; Mine, Keiichiro ; Inoue, Yoshitaka ; Teshima, Miho ; Ogawa, Shuichiro ; Kai, Yuji ; Kurafuji, Toshinobu ; Hirakawa, Kanako ; Miyakawa, Daiki ; Ikeda, Haruka ; Inada, Akari ; Hara, Manami ; Yamada, Hisakata ; Akashi, Koichi ; Niho, Yoshiyuki ; Ina, Keisuke ; Kobayashi, Takashi ; Yoshikai, Yasunobu ; Anzai, Keizo ; Yamashita, Teruo ; Minagawa, Hiroko ; Fujimoto, Shuji ; Kurisaki, Hironori ; Shimoda, Kazuya ; Katsuta, Hitoshi ; Nagafuchi, Seiho. / Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. In: Nature communications. 2015 ; Vol. 6.
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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.",
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