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

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 () and Su-Chang Lin ()
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Chao-Yu Yang: Academia Sinica
Yi-Chun Tseng: Academia Sinica
Yi-Fan Tu: National Cheng Kung University
Bai-Jiun Kuo: National Cheng Kung University
Li-Chung Hsu: 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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53306-1

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