| Author |
Li, XM; Li, F; Zhang, XX; Zhang, HW; Zhao, Q; Li, M; Wu, XX; Wang, LX; Liu, JL; Wu, XH; Ou, YJ; Xing, MY; Zhang, Y; Deng, JS; Wang, XZ; Luo, Y; Li, JB; Zhao, YW; Zhang, HB |
| 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(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. |
