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.
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Acknowledgements
This work was supported by the US National Institutes of Health Director's New Innovator Award DP2 OD001925 (F.R.P.), RO1 DK080955 (F.R.P.), RO1 CA136577 (S.A.O.), R00 GM080097 (M.A.S.) and R01 GM086858 (D.J.M.), an American Cancer Society Research Scholar Award (S.A.O.) and the Burroughs Wellcome (F.R.P.), Juvenile Diabetes Research (F.R.P.) and Sloan (D.J.M.) Foundations. S.B.H. was supported by a predoctoral fellowship from the American Heart Association.
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F.R.P. and D.J.M. contributed equally as senior authors to the study. F.R.P. and D.J.M. conceived the idea and designed the study. With the guidance of F.R.P. and D.J.M., L.W. designed and performed the biochemical and cellular studies. B.G.K.P. designed and performed all of the chemical syntheses. S.B.H. performed footprinting experiments. B.B. and S.C.S. performed molecular modeling studies. All authors designed experiments, analyzed data and commented on the manuscript. F.R.P. and D.J.M. cowrote the paper.
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Wang, L., Perera, B., Hari, S. et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat Chem Biol 8, 982–989 (2012). https://doi.org/10.1038/nchembio.1094
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DOI: https://doi.org/10.1038/nchembio.1094
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