Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-34891-w
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Funding
- Canadian Institutes of Health Research [MOP-15291, MOP-15415, MOP-53050, MOP-86750]
- FONDECYT [3160461, 1140549]
- Millennium Institute [P09-015-F]
- FONDAP [15150012]
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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.
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