Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia
Xiao‐Ming Li, Fang Li, Xixi Zhang, Haiwei Zhang, Qun Zhao, Ming Li, Xiaoxia Wu, Lingxia Wang, Jianling Liu, Xuanhui Wu, Yangjing Ou, Mingyan Xing, Yue Zhang, Jiangshan Deng, Xiuzhe Wang, Yan Luo, Jinbao Li, Yuwu Zhao, Haibing Zhang, Haibing Zhang, Haibing Zhang
Abstract
Abstract 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 ΔE385/ΔE385 ). Casp8 ΔE385/ΔE385 cells were expectedly resistant to Fas-induced apoptosis, however, Casp8 Δ E385/ΔE385 cells could switch TNF-α-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(ΔE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8 Δ E385/ΔE385 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 Δ E385/ΔE385 Ripk3 −/− and Casp8 Δ E385/ΔE385 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.