ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.

Molecular Cell
A. ZyryanovaDavid Ron

Abstract

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

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Citations

Mar 4, 2021·Biomolecules·Talya ShachamGerardo Z Lederkremer
May 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Satoshi WatanabeAlexander V Misharin
Jun 10, 2021·Nature Communications·Qi HaoCarmela Sidrauski
Aug 8, 2021·Journal of Cellular and Molecular Medicine·Katarzyna MnichAfshin Samali
Aug 18, 2021·The International Journal of Biochemistry & Cell Biology·Eugenia LicariPaola Falletta
Aug 28, 2021·International Journal of Molecular Sciences·Hiroto YasudaHideaki Hara
Oct 10, 2021·Nature Structural & Molecular Biology·Yahui YanDavid Ron

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Methods Mentioned

BETA
nucleotide exchange
density gradient centrifugation
biolayer interferometry
transfections
biosensors
flow cytometry
transfection

Software Mentioned

ImageJ
FlowJo
ISRIB
Gautomatch
Fiji
PHENIX
MotionCor2
GraphPad Prism
Prism GraphPad
RELION

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