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Updated: Sep 27, 2025
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Rapid In Vivo Fixation and Isolation of Translational Complexes from Eukaryotic Cells
Published on: December 25, 2021
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A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by
Morgane Boone1,2, Lan Wang1,2, Rosalie E Lawrence1,2
1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, United States.
Elife
|April 13, 2022
Summary
Stressors activate the integrated stress response (ISR) by modifying translation factor eIF2. A specific mutation in eIF2B protein mimics this modification, activating the ISR independently of stress signals.
Area of Science:
- Cellular biology
- Molecular biology
- Biochemistry
Background:
- Stressors activate the integrated stress response (ISR) in eukaryotic cells.
- The canonical ISR pathway involves phosphorylation of eukaryotic translation initiation factor 2 (eIF2) by stress-sensing kinases.
- This phosphorylation reduces ternary complex levels, inhibiting mRNA translation initiation.
Purpose of the Study:
- To investigate the role of eIF2B's conformational states in ISR regulation.
- To determine how a specific mutation in eIF2B affects ISR activation.
- To functionally and structurally characterize the H160D mutation in eIF2B's β subunit.
Main Methods:
- Biochemical assays to assess nucleotide exchange on eIF2.
- Structural biology techniques to determine protein conformation.
- Functional studies to evaluate ISR activation.
Main Results:
- The H160D mutation in eIF2B promotes an I-State like conformation, mimicking eIF2-P binding.
- This mutation leads to reduced nucleotide exchange on eIF2, independent of eIF2 phosphorylation.
- The study provides functional and structural evidence for the allosteric A/I-State model of ISR regulation.
Conclusions:
- The H160D mutation in eIF2B is sufficient to activate the ISR without eIF2 phosphorylation.
- This finding supports the model that eIF2B's conformational state is a key determinant of ISR activity.
- Allosteric regulation of eIF2B governs the integrated stress response.
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