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Related Experiment Video

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Author Spotlight: Unlocking the World of Intrinsically Disordered Regions with Cellular Sensing and Responses

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Published on: January 12, 2024

DELE1 oligomerization promotes integrated stress response activation.

Jie Yang¹, Kelsey R Baron², Daniel E Pride¹

¹Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.

Nature Structural & Molecular Biology

|August 7, 2023

Summary

Mitochondrial stress triggers DELE1 release, initiating integrated stress response (ISR) signaling. Cryo-EM reveals DELE1 forms an octamer essential for HRI kinase activation and cellular stress response.

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Area of Science:

Cellular Biology
Molecular Biology
Structural Biology

Background:

Mitochondria are key regulators of cellular stress responses.
Mitochondrial stress signaling involves DELE1 and the integrated stress response (ISR).
The DELE1 fragment activates the eIF2α kinase HRI.

Purpose of the Study:

To determine the structure of the DELE1 oligomer.
To elucidate the molecular mechanism of DELE1-mediated ISR activation.
To identify key residues involved in DELE1 oligomerization and function.

Main Methods:

Cryo-electron microscopy (cryo-EM) for structural determination.
Mutagenesis studies to assess the role of key residues.
Cell culture models to evaluate ISR activation.

Main Results:

The C-terminal fragment of human DELE1 forms a stable D4-symmetric octamer.
Specific hydrophobic interactions mediate DELE1 monomer assembly into the octamer.
Mutations impairing DELE1 oligomerization abolish HRI-dependent ISR activation.

Conclusions:

DELE1 oligomerization is critical for its function in relaying mitochondrial stress signals.
The octameric structure provides molecular insights into DELE1's role in ISR.
DELE1 assembly is essential for activating HRI and promoting cellular adaptation to mitochondrial insult.