DELE1 oligomerization promotes integrated stress response activation.

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.