Abstract
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 IRE1α, leading to IRE1α 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 IRE1α branch of the UPR. Cyclosporine-dependent activation of COX-2 and IRE1α in mice indicated that cyclosporine-COX-2-IRE1α signaling pathway was functional in vivo. These findings identify COX-2 as a new IRE1α binding partner and regulator of the IRE1α branch of the UPR pathway, and establishes the mechanism underlying cytotoxicity associated with chronic cyclosporine exposure.
Highlights
endoplasmic reticulum (ER) stress is caused by many intrinsic or extrinsic factors that disturb ER homeostasis and functions, leading to activation of the unfolded protein response (UPR), an ER stress coping response
We tested for effects of silencing of COX-2 mRNA on Inositol-requiring enzyme 1α (IRE1α)-dependent splicing of XBP1 mRNA, a measure of IRE1α activity and an indicator of UPR activation[31]
We identified COX-2 as a novel target for cyclosporine and established that COX-2 interacts with IRE1α, an ER associated stress sensor and component of the UPR, to activate IRE1α
Summary
ER stress is caused by many intrinsic or extrinsic factors that disturb ER homeostasis and functions, leading to activation of the unfolded protein response (UPR), an ER stress coping response. Inositol-requiring enzyme 1α (IRE1α) is an ER transmembrane protein kinase and the most evolutionary conserved ER stress sensor and component of the UPR. Cyclosporine inhibits the immune response upon inflammatory stimuli by binding to cyclophilin A, a cytoplasmic peptidyl prolyl isomerase enzyme, with the complex associating with and inhibiting calcineurin, a protein serine/threonine phosphatase. This interaction prevents the de-phosphorylation of NF-AT, its translocation to the nucleus and the stimulation of genes responsible for the activation of T-cells[10]. These findings revealed a new and unanticipated cyclosporine-dependent signaling pathway and provide a mechanism for how cyclosporine and COX-2 activate the IRE1α branch of the UPR pathway
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
