A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress.
Unfolded proteins in the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1alpha, 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 IRE1alpha 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 IRE1alpha kinase through this maneuver affords murine cells cytoprotection under ER stress. Thus kinase inhibitors of IRE1alpha are useful for altering the apoptotic outcome to ER stress, and could possibly be developed into drugs to treat ER stress-related diseases.
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-2520, USA.
Dan
D
Han
John-Paul
JP
Upton
Andrew
A
Hagen
Joseph
J
Callahan
Scott A
SA
Oakes
Feroz R
FR
Papa
D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004722:Endoribonucleases / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases