RRC ID 35933
Author 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.
Title Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.
Journal Nat Commun
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.
Volume 6
Pages 6748
Published 2015-4-7
DOI 10.1038/ncomms7748
PII ncomms7748
PMID 25849081
PMC PMC4396380
MeSH Animals Cardiovirus Infections / genetics* Diabetes Mellitus, Experimental / genetics* Diabetes Mellitus, Experimental / virology Encephalomyocarditis virus* Gene Expression Genetic Predisposition to Disease Insulin-Secreting Cells / metabolism* Interferon Type I Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Mutation RNA, Messenger / metabolism* TYK2 Kinase / genetics* TYK2 Kinase / metabolism
IF 12.121
Times Cited 26
DNA material pGL4.17 Tyk2 WT (RDB13913) pGL4.17 Tyk2 mutant (RDB13914).