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 language | English |
|---|---|
| Pages (from-to) | 982-989 |
| Number of pages | 8 |
| Journal | Nature Chemical Biology |
| Volume | 8 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2012 |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
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 journal › Article
}
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.
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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 -