期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-34891-w
关键词
-
资金
- Canadian Institutes of Health Research [MOP-15291, MOP-15415, MOP-53050, MOP-86750]
- FONDECYT [3160461, 1140549]
- Millennium Institute [P09-015-F]
- FONDAP [15150012]
Cyclosporine, a widely used immunosuppressant in organ transplantation and in treatment of various autoimmune diseases, activates the unfolded protein response (UPR), an ER stress coping response. In this study we discovered a new and unanticipated cyclosporine-dependent signaling pathway, with cyclosporine triggering direct activation of the UPR. COX-2 binds to and activates IRE1 alpha, leading to IRE1 alpha splicing of XBP1 mRNA. Molecular interaction and modeling analyses identified a novel interaction site for cyclosporine with COX-2 which caused enhancement of COX-2 enzymatic activity required for activation of the IREloi branch of the UPR. Cyclosporine-dependent activation of COX-2 and IRE1 alpha in mice indicated that cyclosporine-COX-2-IRE1 alpha signaling pathway was functional in vivo. These findings identify COX-2 as a new IRE1 alpha binding partner and regulator of the IRE1 alpha branch of the UPR pathway, and establishes the mechanism underlying cytotoxicity associated with chronic cyclosporine exposure.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据