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Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis

Author

Listed:
  • Chao-Yu Yang

    (Academia Sinica)

  • Chia-I Lien

    (National Taiwan University)

  • Yi-Chun Tseng

    (Academia Sinica
    National Cheng Kung University)

  • Yi-Fan Tu

    (National Cheng Kung University)

  • Arkadiusz W. Kulczyk

    (Rutgers University)

  • Yen-Chen Lu

    (National Cheng Kung University)

  • Yin-Ting Wang

    (Academia Sinica)

  • Tsung-Wei Su

    (Academia Sinica)

  • Li-Chung Hsu

    (National Taiwan University
    National Taiwan University)

  • Yu-Chih Lo

    (National Cheng Kung University)

  • Su-Chang Lin

    (Academia Sinica)

Abstract

Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.

Suggested Citation

  • Chao-Yu Yang & Chia-I Lien & Yi-Chun Tseng & Yi-Fan Tu & Arkadiusz W. Kulczyk & Yen-Chen Lu & Yin-Ting Wang & Tsung-Wei Su & Li-Chung Hsu & Yu-Chih Lo & Su-Chang Lin, 2024. "Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47990-2
    DOI: 10.1038/s41467-024-47990-2
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    References listed on IDEAS

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