Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia

Li, Xiaoming1; Li, Fang2,3; Zhang, Xixi1; Zhang, Haiwei1; Zhao, Qun1; Li, Ming1; Wu, Xiaoxia1; Wang, Lingxia1; Liu, Jianling1; Wu, Xuanhui1; Ou, Yangjing1; Xing, Mingyan1; Zhang, Yue4; Deng, Jiangshan5; Wang, Xiuzhe5; Luo, Yan4; Li, Jinbao2; Zhao, Yuwu5; Zhang, Haibing1

2022

10.1038/s41418-022-00938-9

CELL DEATH AND DIFFERENTIATION   影响因子和分区

1350-9047

1476-5403

Caspase-8 is an initiator of death receptor-induced apoptosis and an inhibitor of RIPK3-MLKL-dependent necroptosis. In addition, caspase-8 has been implicated in diseases such as lymphoproliferation, immunodeficiency, and autoimmunity in humans. Although auto-cleavage is indispensable for caspase-8 activation, its physiological functions remain poorly understood. Here, we generated a caspase-8 mutant lacking E385 in auto-cleavage site knock-in mouse (Casp8(Delta E385/Delta E385)). Casp8(Delta E385/Delta E385) cells were expectedly resistant to Fas-induced apoptosis, however, Casp8(Delta E385/Delta E385) cells could switch TNF-alpha-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(Delta E385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8(Delta E385/Delta E385)Ripk3(-/-) mice partially rescued the perinatal death of Ripk1(-/-) mice by blocking apoptosis and necroptosis. In contrast to the Casp8(-/-)Ripk3(-/-) and Casp8(-/-)Mlkl(-/-) mice appearing autoimmune lymphoproliferative syndrome (ALPS), both Casp8(Delta E385/Delta E385)Ripk3(-/-) and Casp8(Delta E385/Delta E385)Mlkl(-/-) mice developed transplantable lymphopenia that could be significantly reversed by RIPK1 heterozygosity, but not by RIPK1 kinase dead mutation. Collectively, these results demonstrate previously unappreciated roles for caspase-8 auto-cleavage in regulating necroptosis and maintaining lymphocytes homeostasis.

SCI

英语

其他

Strategic Priority Research Program of Chinese Academy of Sciences[XDA26040306] ; National Natural Science Foundation of China[31970688,31771537,82001684,81871101] ; National Key Research and Development Program of China["2018YFC1200201","2016YFC1304900"]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000745403400001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China
2.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Anesthesiol, Sch Med, Shanghai, Peoples R China
3.Southern Univ Sci & Technol, Sch Med, Affiliated Hosp 2, Shenzhen, Peoples R China
4.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Anesthesiol, Sch Med, Shanghai, Peoples R China
5.Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Neurol, Shanghai, Peoples R China

Li, Xiaoming,Li, Fang,Zhang, Xixi,et al. Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia[J]. CELL DEATH AND DIFFERENTIATION,2022.

Li, Xiaoming.,Li, Fang.,Zhang, Xixi.,Zhang, Haiwei.,Zhao, Qun.,...&Zhang, Haibing.(2022).Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia.CELL DEATH AND DIFFERENTIATION.

Li, Xiaoming,et al."Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia".CELL DEATH AND DIFFERENTIATION (2022).