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Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates the IRE1α unfolded protein response sensor.

Sci Rep. 2018; 
Groenendyk J, Paskevicius T, Urra H,,, Viricel C, Wang K, Barakat K, Hetz C,,,,, Kurgan L, Agellon LB, Michalak M.
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Mutagenesis Services The single site mutation H374Y was generated by Genscript and was cloned in the pCMV6 plasmid for mammalian expression.... Single site mutagenesis to generate the COX-2 H374Y mutant was performed by GenScript and transformed E. Get A Quote

摘要

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 th... More

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