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Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes

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  • Chao-Yu Yang

    (Academia Sinica)

  • Yi-Chun Tseng

    (Academia Sinica
    National Cheng Kung University)

  • Yi-Fan Tu

    (National Cheng Kung University)

  • Bai-Jiun Kuo

    (National Cheng Kung University)

  • Li-Chung Hsu

    (National Taiwan University
    National Taiwan University)

  • Chia-I Lien

    (National Taiwan University)

  • You-Sheng Lin

    (National Taiwan University)

  • Yin-Ting Wang

    (Academia Sinica)

  • Yen-Chen Lu

    (National Cheng Kung University)

  • Tsung-Wei Su

    (Academia Sinica)

  • Yu-Chih Lo

    (National Cheng Kung University)

  • Su-Chang Lin

    (Academia Sinica)

Abstract

cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.

Suggested Citation

  • Chao-Yu Yang & Yi-Chun Tseng & Yi-Fan Tu & Bai-Jiun Kuo & Li-Chung Hsu & Chia-I Lien & You-Sheng Lin & Yin-Ting Wang & Yen-Chen Lu & Tsung-Wei Su & Yu-Chih Lo & Su-Chang Lin, 2024. "Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53306-1
    DOI: 10.1038/s41467-024-53306-1
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    1. William J. Kaiser & Jason W. Upton & Alyssa B. Long & Devon Livingston-Rosanoff & Lisa P. Daley-Bauer & Razqallah Hakem & Tamara Caspary & Edward S. Mocarski, 2011. "RIP3 mediates the embryonic lethality of caspase-8-deficient mice," Nature, Nature, vol. 471(7338), pages 368-372, March.
    2. Matthias Eberstadt & Baohua Huang & Zehan Chen & Robert P. Meadows & Shi-Chung Ng & Lixin Zheng & Michael J. Lenardo & Stephen W. Fesik, 1998. "NMR structure and mutagenesis of the FADD (Mort1) death-effector domain," Nature, Nature, vol. 392(6679), pages 941-945, April.
    3. Andrew Oberst & Christopher P. Dillon & Ricardo Weinlich & Laura L. McCormick & Patrick Fitzgerald & Cristina Pop & Razq Hakem & Guy S. Salvesen & Douglas R. Green, 2011. "Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis," Nature, Nature, vol. 471(7338), pages 363-367, March.
    4. 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.
    5. Marius Dannappel & Katerina Vlantis & Snehlata Kumari & Apostolos Polykratis & Chun Kim & Laurens Wachsmuth & Christina Eftychi & Juan Lin & Teresa Corona & Nicole Hermance & Matija Zelic & Petra Kirs, 2014. "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis," Nature, Nature, vol. 513(7516), pages 90-94, September.
    6. Martin Irmler & Margot Thome & Michael Hahne & Pascal Schneider & Kay Hofmann & Véronique Steiner & Jean-Luc Bodmer & Michael Schröter & Kim Burns & Chantal Mattmann & Donata Rimoldi & Lars E. French , 1997. "Inhibition of death receptor signals by cellular FLIP," Nature, Nature, vol. 388(6638), pages 190-195, July.
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