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

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 () and Su-Chang Lin ()
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Chao-Yu Yang: Academia Sinica
Chia-I Lien: National Taiwan University
Yi-Chun Tseng: Academia Sinica
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
Yu-Chih Lo: National Cheng Kung University
Su-Chang Lin: Academia Sinica

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47990-2

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