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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Catalysis
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Cells, Cultured
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Cross-Linking Reagents
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Endoplasmic Reticulum Stress / physiology
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Endoribonucleases / antagonists & inhibitors*
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Humans
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Molecular Conformation
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Mutation / genetics
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Mutation / physiology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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RNA Splicing / drug effects
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Regulatory Factor X Transcription Factors
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Ribonucleases / metabolism
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Transcription Factors / metabolism
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Unfolded Protein Response / drug effects
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Up-Regulation / drug effects
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X-Box Binding Protein 1
Substances
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Adaptor Proteins, Signal Transducing
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CTNNBIP1 protein, human
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Cross-Linking Reagents
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Protein Kinase Inhibitors
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Regulatory Factor X Transcription Factors
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Ribonucleases
Associated data
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PubChem-Substance/144203443
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PubChem-Substance/144203444
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PubChem-Substance/144203445
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PubChem-Substance/144203446
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PubChem-Substance/144203447
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PubChem-Substance/144203448
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PubChem-Substance/144203449
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PubChem-Substance/144203450