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Interaction between DLC-1 and SAO-1 facilitates CED-4 translocation during apoptosis in the Caenorhabditis elegans
Dandan Zhang1,2,3, Haibin Yang2,3, Ling Jiang2,3,4
1School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
Abstract:
Apoptosis is one of the major forms of programmed cell death, and it serves vital biological functions in multicellular animal and plant cells. The core mechanism of apoptosis is highly conserved in metazoans, where the translocation of CED-4/Apaf-1 from mitochondria to the nuclear membrane is required to initiate and execute apoptosis. However, the underlying molecular mechanisms of this translocation are poorly understood. In this study, we showed that SAO-1 binds DLC-1 and prevents its degradation to promote apoptosis in C. elegans germ cells. We demonstrated that SAO-1 and DLC-1 regulate CED-4/Apaf-1 nuclear membrane accumulation during apoptosis. Isothermal titration calorimetry-based assay and high-resolution crystal structure analysis further revealed that SAO-1 interacted with DLC-1 to form a 2:4 complex: each of the two β-sheets in the SAO-1 peptide interacted with two DLC-1 dimers. Point mutations at the SAO-1-DLC-1 binding interface significantly inhibited apoptotic corpse formation and CED-4 nuclear membrane accumulation within C. elegans germ cells. In conclusion, our study provides a new perspective on the regulation of CED-4-mediated apoptosis.
Insights
SAO-1 binds DLC-1, preventing its degradation and promoting apoptosis in C. elegans germ cells. This interaction is crucial for regulating CED-4/Apaf-1 nuclear membrane accumulation during programmed cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Apoptosis, a fundamental programmed cell death process, is essential for multicellular organisms.
- The translocation of CED-4/Apaf-1 to the nuclear membrane initiates apoptosis in metazoans, but its regulation is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating CED-4/Apaf-1 translocation during apoptosis.
- To investigate the roles of SAO-1 and DLC-1 in programmed cell death in C. elegans.
Main Methods:
- Isothermal titration calorimetry (ITC) to analyze protein interactions.
- High-resolution crystal structure analysis to determine complex formation.
- Genetic manipulation and phenotypic analysis in C. elegans germ cells.
Main Results:
- SAO-1 binds DLC-1, inhibiting DLC-1 degradation and promoting apoptosis.
- SAO-1 and DLC-1 are key regulators of CED-4/Apaf-1 nuclear membrane accumulation.
- Structural analysis revealed a 2:4 complex of SAO-1 and DLC-1, with specific binding interfaces critical for function.
- Mutations disrupting the SAO-1-DLC-1 interaction impaired apoptosis and CED-4 localization.
Conclusions:
- SAO-1 and DLC-1 form a complex that regulates CED-4-mediated apoptosis.
- This study provides novel insights into the molecular control of programmed cell death initiation.
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