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Updated: Jul 16, 2025

Measurements of Physiological Stress Responses in C. Elegans

Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

eIF3d controls the persistent integrated stress response.

Shaoni Mukhopadhyay¹, Maria E Amodeo¹, Amy S Y Lee¹

¹Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

|September 8, 2023

Summary

The integrated stress response (ISR) relies on eIF3d, a protein that controls key stress factors. eIF3d orchestrates cellular survival during chronic stress by regulating protein synthesis and gene expression.

Keywords:

ATF4 GCN2 RNA methylation eIF3d integrated stress response m(6)A translation regulation

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Area of Science:

Cellular Biology
Molecular Biology
Stress Response Mechanisms

Background:

Cells activate survival pathways, including the integrated stress response (ISR), to cope with intrinsic and extrinsic stresses.
The ISR involves reduced global protein synthesis and activation of specific gene programs.

Purpose of the Study:

To elucidate the role of the non-canonical cap-binding protein eIF3d in driving the ISR.
To identify how eIF3d controls key stress response factors like eIF2α and ATF4.

Main Methods:

Investigated the function of eIF3d in cellular stress models.
Analyzed the impact of eIF3d on translation factors (eIF2α, GCN2) and transcription factors (ATF4).
Examined the regulation of mRNA demethylation by ALKBH5 and its effect on stress response genes.

Main Results:

eIF3d activates GCN2 translation, leading to eIF2α phosphorylation and inhibition of general protein synthesis during persistent stress.
eIF3d upregulates ALKBH5, promoting 5' UTR-specific demethylation of stress genes like ATF4.
This cascade enhances ATF4 expression by improving mRNA engagement and ribosome bypass of uORFs.

Conclusions:

eIF3d acts as a critical effector in the ISR, controlling both translation and transcription.
eIF3d functions at a crucial decision point during chronic stress, balancing cellular survival.
A synergistic mechanism involving translational and transcriptional regulation amplifies cellular responses to stress.