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; Seiho Nagafuchi

doi:10.1038/ncomms7748

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

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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 language	English
Article number	6748
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7748
Publication status	Published - Apr 13 2015

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

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10.1038/ncomms7748

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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., ... Nagafuchi, S. (2015). Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. Nature communications, 6, Article 6748. https://doi.org/10.1038/ncomms7748

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

@article{e64209295df44974b368c71e3ea07075,

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.",

author = "Kenichi Izumi and Keiichiro Mine and Yoshitaka Inoue and Miho Teshima and Shuichiro Ogawa and Yuji Kai and Toshinobu Kurafuji and Kanako Hirakawa and Daiki Miyakawa and Haruka Ikeda and Akari Inada and Manami Hara and Hisakata Yamada and Koichi Akashi and Yoshiyuki Niho and Keisuke Ina and Takashi Kobayashi and Yasunobu Yoshikai and Keizo Anzai and Teruo Yamashita and Hiroko Minagawa and Shuji Fujimoto and Hironori Kurisaki and Kazuya Shimoda and Hitoshi Katsuta and Seiho Nagafuchi",

note = "Funding Information: We thank Itsuka Matsumoto, Ai Umei, Miki Kawano, Makoto Matsuo, Hiroko Hamada, Yumi Kamada, Yasuko Kajiki, Kanade Tokuzumim, Yukari Shimoda, Takamitsu Kasagi, Airsa Moroishi and Drs Yuji Ueki, Kazunobu Amako, Kaoru Aida and Tetsuro Kobayashi for their help in conducting this research. We also thank Drs Angela Koh and Chiri Nagatsuka for their help in preparing the manuscript. We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. This work was supported by grants (19209037 and 21659230) from the Ministry of Education, Culture, Sports, Science and Technology and a grant from the Ministry of Health, Labor, and Welfare of Japan. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = apr,

day = "13",

doi = "10.1038/ncomms7748",

language = "English",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

AU - Izumi, Kenichi

AU - Mine, Keiichiro

AU - Inoue, Yoshitaka

AU - Teshima, Miho

AU - Ogawa, Shuichiro

AU - Kai, Yuji

AU - Kurafuji, Toshinobu

AU - Hirakawa, Kanako

AU - Miyakawa, Daiki

AU - Ikeda, Haruka

AU - Inada, Akari

AU - Hara, Manami

AU - Yamada, Hisakata

AU - Akashi, Koichi

AU - Niho, Yoshiyuki

AU - Ina, Keisuke

AU - Kobayashi, Takashi

AU - Yoshikai, Yasunobu

AU - Anzai, Keizo

AU - Yamashita, Teruo

AU - Minagawa, Hiroko

AU - Fujimoto, Shuji

AU - Kurisaki, Hironori

AU - Shimoda, Kazuya

AU - Katsuta, Hitoshi

AU - Nagafuchi, Seiho

N1 - Funding Information: We thank Itsuka Matsumoto, Ai Umei, Miki Kawano, Makoto Matsuo, Hiroko Hamada, Yumi Kamada, Yasuko Kajiki, Kanade Tokuzumim, Yukari Shimoda, Takamitsu Kasagi, Airsa Moroishi and Drs Yuji Ueki, Kazunobu Amako, Kaoru Aida and Tetsuro Kobayashi for their help in conducting this research. We also thank Drs Angela Koh and Chiri Nagatsuka for their help in preparing the manuscript. We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. This work was supported by grants (19209037 and 21659230) from the Ministry of Education, Culture, Sports, Science and Technology and a grant from the Ministry of Health, Labor, and Welfare of Japan. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/4/13

Y1 - 2015/4/13

N2 - 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.

AB - 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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JO - Nature communications

JF - Nature communications

M1 - 6748

ER -

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

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