Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors

Likun Wang, B. Gayani K Perera, Sanjay B. Hari, Barun Bhhatarai, Bradley J. Backes, Markus A. Seeliger, Stephan C Schuerer, Scott A. Oakes, Feroz R. Papa, Dustin J. Maly

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)982-989
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2012

Fingerprint

Endoribonucleases
Ribonucleases
Endoplasmic Reticulum Stress
Phosphotransferases
Unfolded Protein Response
Adenosine Triphosphate
Binding Sites
Protein Unfolding
Messenger RNA
Endoplasmic Reticulum
Ligands
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Wang, L., Perera, B. G. K., Hari, S. B., Bhhatarai, B., Backes, B. J., Seeliger, M. A., ... Maly, D. J. (2012). Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nature Chemical Biology, 8(12), 982-989. https://doi.org/10.1038/nchembio.1094

Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. / Wang, Likun; Perera, B. Gayani K; Hari, Sanjay B.; Bhhatarai, Barun; Backes, Bradley J.; Seeliger, Markus A.; Schuerer, Stephan C; Oakes, Scott A.; Papa, Feroz R.; Maly, Dustin J.

In: Nature Chemical Biology, Vol. 8, No. 12, 01.12.2012, p. 982-989.

Research output: Contribution to journalArticle

Wang, L, Perera, BGK, Hari, SB, Bhhatarai, B, Backes, BJ, Seeliger, MA, Schuerer, SC, Oakes, SA, Papa, FR & Maly, DJ 2012, 'Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors', Nature Chemical Biology, vol. 8, no. 12, pp. 982-989. https://doi.org/10.1038/nchembio.1094
Wang L, Perera BGK, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nature Chemical Biology. 2012 Dec 1;8(12):982-989. https://doi.org/10.1038/nchembio.1094
Wang, Likun ; Perera, B. Gayani K ; Hari, Sanjay B. ; Bhhatarai, Barun ; Backes, Bradley J. ; Seeliger, Markus A. ; Schuerer, Stephan C ; Oakes, Scott A. ; Papa, Feroz R. ; Maly, Dustin J. / Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 12. pp. 982-989.
@article{f90598ce72024ed89826a1504b6a7388,
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.",
author = "Likun Wang and Perera, {B. Gayani K} and Hari, {Sanjay B.} and Barun Bhhatarai and Backes, {Bradley J.} and Seeliger, {Markus A.} and Schuerer, {Stephan C} and Oakes, {Scott A.} and Papa, {Feroz R.} and Maly, {Dustin J.}",
year = "2012",
month = "12",
day = "1",
doi = "10.1038/nchembio.1094",
language = "English",
volume = "8",
pages = "982--989",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors

AU - Wang, Likun

AU - Perera, B. Gayani K

AU - Hari, Sanjay B.

AU - Bhhatarai, Barun

AU - Backes, Bradley J.

AU - Seeliger, Markus A.

AU - Schuerer, Stephan C

AU - Oakes, Scott A.

AU - Papa, Feroz R.

AU - Maly, Dustin J.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870357261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870357261&partnerID=8YFLogxK

U2 - 10.1038/nchembio.1094

DO - 10.1038/nchembio.1094

M3 - Article

C2 - 23086298

AN - SCOPUS:84870357261

VL - 8

SP - 982

EP - 989

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 12

ER -