Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.
Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.
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由于自然突变而导致的β细胞中TYK2基因表达降低决定了对病毒诱导的糖尿病的敏感性。
DOI：
10.1038/ncomms7748
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发表时间：
2015-04-07
影响因子：
16.6
通讯作者：
Nagafuchi, Seiho
中科院分区：
文献类型：
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作者：
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
越来越多的证据表明，病毒在糖尿病的发展中起着重要作用。虽然糖尿病致脑心肌炎D株病毒可在近交系小鼠中诱发糖尿病，但病毒诱导的糖尿病的易感基因尚未确定。我们在此报告在病毒诱导的糖尿病敏感型SJL和SWR小鼠中存在新的酪氨酸激酶2(TYK2)基因突变。在抗病毒的C57BL/6背景上携带突变TYK2基因的小鼠对病毒诱导的糖尿病高度敏感。在TYK2突变小鼠中，TYK2基因的表达显著降低，与TYK2启动子活性低相关，并导致干扰素诱导基因的表达减少，导致显著的抗病毒反应。突变的胰腺β细胞即使对高剂量的I型干扰素也没有反应。通过β细胞特异性TYK2基因的表达可以逆转病毒诱导的糖尿病。因此，自然突变导致胰腺β-细胞中TYK2基因表达减少是导致病毒诱导糖尿病易感性的原因。糖尿病可由人类和一些近亲繁殖的小鼠的病毒感染引起，这表明存在遗传易感性。在这里，作者表明，TYK2基因突变是导致小鼠对病毒诱导的糖尿病易感性的基础，这是由于TYK2需要胰岛素产生细胞的抗病毒反应。
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. Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2 requirement for antiviral response in insulin-producing cells.
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影响因子：
15.3
作者：
BOUCHER, DW;NOTKINS, AL
通讯作者：
NOTKINS, AL
DOI：
10.1152/ajpendo.00321.2002
发表时间：
2003-01-01
影响因子：
5.1
作者：
Hara, M;Wang, XY;Bell, GI
通讯作者：
Bell, GI
影响因子：
7.7
作者：
ROSS, ME;ONODERA, T;NOTKINS, AL
通讯作者：
NOTKINS, AL
影响因子：
15.9
作者：
McCartney, Stephen A.;Vermi, William;Colonna, Marco
通讯作者：
Colonna, Marco
影响因子：
5.4
作者：
Jun, HS;Kang, Y;Yoon, JW
通讯作者：
Yoon, JW