A kinase inhibitor activates the IRE1α RNase to confer cytoprotection against ER stress
详细信息 查看全文
- 作者：Dan Han ; John-Paul Upton ; Andrew Hagen ; Joseph Callahan ; Scott A. Oakes ; Feroz R. Papa
- 关键词：Endoplasmic reticulum ; Kinase ; Protein-folding disease ; Inhibitor ; Endoribonuclease
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2008
- 出版时间：25 January 2008
- 年：2008
- 卷：365
- 期：4
- 页码：777-783
- 全文大小：445 K
文摘
Unfolded proteins in the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1α, inducing its RNase activity to splice XBP1 mRNA, in turn triggering a transcriptional program in the unfolded protein response (UPR). As we previously showed with the yeast IRE1 kinase ortholog, a single missense mutation in the ATP-binding pocket of murine IRE1α kinase sensitizes it to the ATP-competitive inhibitor 1NM-PP1, and subordinates RNase activity to the drug. This highly unusual mechanism of kinase signaling requiring kinase domain ligand occupancy—even through an inhibitor—to activate a nearby RNase has therefore been completely conserved through evolution. We also demonstrate that engagement of the drug-sensitized IRE1α kinase through this maneuver affords murine cells cytoprotection under ER stress. Thus kinase inhibitors of IRE1α are useful for altering the apoptotic outcome to ER stress, and could possibly be developed into drugs to treat ER stress-related diseases.