title: Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors.
abstract: Under endoplasmic reticulum stress, unfolded protein accumulation leads to activation of the endoplasmic reticulum transmembrane kinase/endoRNase (RNase) IRE1α. IRE1α oligomerizes, autophosphorylates and initiates splicing of XBP1 mRNA, thus triggering the unfolded protein response (UPR). Here we show that IRE1α's kinase-controlled RNase can be regulated in two distinct modes with kinase inhibitors: one class of ligands occupies IRE1α's kinase ATP-binding site to activate RNase-mediated XBP1 mRNA splicing even without upstream endoplasmic reticulum stress, whereas a second class can inhibit the RNase through the same ATP-binding site, even under endoplasmic reticulum stress. Thus, alternative kinase conformations stabilized by distinct classes of ATP-competitive inhibitors can cause allosteric switching of IRE1α's RNase--either on or off. As dysregulation of the UPR has been implicated in a variety of cell degenerative and neoplastic disorders, small-molecule control over IRE1α should advance efforts to understand the UPR's role in pathophysiology and to develop drugs for endoplasmic reticulum stress-related diseases.
authors.affiliation: Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
authors.forename: Likun
authors.initials: L
authors.lastname: Wang
authors.forename: B Gayani K
authors.initials: BG
authors.lastname: Perera
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Hari
authors.forename: Barun
authors.initials: B
authors.lastname: Bhhatarai
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schürer
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002384:Catalysis; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008968:Molecular Conformation; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012326:RNA Splicing / Q000187:drug effects; D000071701:Regulatory Factor X Transcription Factors; D012260:Ribonucleases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C411982:CTNNBIP1 protein, human; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D012260:Ribonucleases