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

Author

Listed:
  • Shuo-Shuo Liu

    (Beijing Normal University)

  • Tian-Xia Jiang

    (Beijing Normal University)

  • Fan Bu

    (Beijing Normal University)

  • Ji-Lan Zhao

    (Beijing Normal University)

  • Guang-Fei Wang

    (Beijing Normal University)

  • Guo-Heng Yang

    (Beijing Normal University)

  • Jie-Yan Kong

    (Beijing Normal University)

  • Yun-Fan Qie

    (Beijing Normal University)

  • Pei Wen

    (China Pharmaceutical University
    Anhui Medical University)

  • Li-Bin Fan

    (Anhui Medical University)

  • Ning-Ning Li

    (Peking University)

  • Ning Gao

    (Peking University)

  • Xiao-Bo Qiu

    (Beijing Normal University
    China Pharmaceutical University)

Abstract

Procaspase 9 is the initiator caspase for apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor-of-Apoptosis Protein BIRC6/BRUCE/Apollon inhibits both apoptosis and autophagy by promoting ubiquitylation of proapoptotic factors and the key autophagic protein LC3, respectively. Here we show that BIRC6 forms an anti-parallel U-shaped dimer with multiple previously unannotated domains, including a ubiquitin-like domain, and the proapoptotic factor Smac/DIABLO binds BIRC6 in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not procaspase 9, for binding BIRC6 in cells. BIRC6 also binds LC3 through its LC3-interacting region, probably following dimer disruption of this BIRC6 region. Mutation at LC3 ubiquitylation site promotes autophagy and autophagic degradation of BIRC6. Moreover, induction of autophagy promotes autophagic degradation of BIRC6 and caspase 9, but not of other effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

Suggested Citation

  • Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45222-1
    DOI: 10.1038/s41467-024-45222-1
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