Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 12, Pages 982-989Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1094
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Funding
- US National Institutes of Health Director's New Innovator Award [DP2 OD001925, RO1 DK080955, RO1 CA136577, R00 GM080097, R01 GM086858]
- American Cancer Society Research Scholar Award
- Burroughs Wellcome Foundation
- Juvenile Diabetes Research Foundation
- Sloan Foundation
- American Heart Association
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Under endoplasmic reticulum stress, unfolded protein accumulation leads to activation of the endoplasmic reticulum transmembrane kinase/endoRNase (RNase) IRE1 alpha. IRE1 alpha oligomerizes, autophosphorylates and initiates splicing of XBP1 mRNA, thus triggering the unfolded protein response (UPR). Here we show that IRE1 alpha's kinase-controlled RNase can be regulated in two distinct modes with kinase inhibitors: one class of ligands occupies IRE1 alpha'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 IRE1 alpha'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 IRE1 alpha 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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