| First Author | Groenendyk J | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 16678 |
| PubMed ID | 30420769 | Mgi Jnum | J:269962 |
| Mgi Id | MGI:6271726 | Doi | 10.1038/s41598-018-34891-w |
| Citation | Groenendyk J, et al. (2018) Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates the IRE1alpha unfolded protein response sensor. Sci Rep 8(1):16678 |
| abstractText | 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 IRE1alpha, leading to IRE1alpha 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 IRE1alpha branch of the UPR. Cyclosporine-dependent activation of COX-2 and IRE1alpha in mice indicated that cyclosporine-COX-2-IRE1alpha signaling pathway was functional in vivo. These findings identify COX-2 as a new IRE1alpha binding partner and regulator of the IRE1alpha branch of the UPR pathway, and establishes the mechanism underlying cytotoxicity associated with chronic cyclosporine exposure. |
