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Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy

Shuo-Shuo Liu1, Tian-Xia Jiang1, Fan Bu1

  • 1State Key Laboratory of Cognitive Neuroscience & Learning and Ministry of Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing, 100875, China.

Nature Communications
|January 30, 2024
PubMed

Insights

The Inhibitor-of-Apoptosis Protein BIRC6 regulates apoptosis and autophagy by binding Smac/DIABLO and LC3. Autophagy induction degrades BIRC6 and caspase 9, impacting cell death pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Procaspase 9 initiates apoptosis, but its regulation is unclear.
  • Inhibitor-of-Apoptosis Protein BIRC6 (also known as BRUCE or Apollon) inhibits apoptosis and autophagy.
  • BIRC6 targets proapoptotic factors and LC3 for ubiquitylation, controlling cell death and self-eating pathways.

Purpose of the Study:

  • To elucidate the structural basis of BIRC6 function.
  • To investigate the interactions of BIRC6 with key regulatory proteins like Smac/DIABLO, caspase 3, HtrA2, and LC3.
  • To understand how BIRC6 regulates the balance between apoptosis and autophagy.

Main Methods:

  • Structural analysis of BIRC6 dimer formation.
  • Co-immunoprecipitation assays to study protein-protein interactions in cells.
  • Site-directed mutagenesis to investigate the role of the LC3-interacting region and ubiquitylation sites.
  • Autophagy induction experiments and Western blotting to assess protein degradation.

Main Results:

  • BIRC6 forms an anti-parallel U-shaped dimer with unannotated domains, including a ubiquitin-like domain.
  • The proapoptotic factor Smac/DIABLO binds BIRC6's central cavity, outcompeting effector caspases 3 and HtrA2 but not procaspase 9.
  • BIRC6 binds LC3 via its LC3-interacting region, and mutations disrupting LC3 ubiquitylation promote autophagy and BIRC6 degradation.

Conclusions:

  • BIRC6's structure facilitates interactions with Smac/DIABLO, modulating apoptosis.
  • Autophagy induction leads to the degradation of BIRC6 and caspase 9, highlighting a regulatory link between these pathways.
  • These findings provide insights into the complex regulation of apoptosis and autophagy under various conditions.

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