Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia.
Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia.
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Caspase-8 自动裂解调节程序性细胞死亡并与 RIPK3/MLKL 合作预防淋巴细胞减少
DOI：
10.1038/s41418-022-00938-9
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发表时间：
2022-08
影响因子：
12.4
通讯作者：
Zhang, Haibing
中科院分区：
文献类型：
--
作者：
Li, Xiaoming;Li, Fang;Zhang, Xixi;Zhang, Haiwei;Zhao, Qun;Li, Ming;Wu, Xiaoxia;Wang, Lingxia;Liu, Jianling;Wu, Xuanhui;Ou, Yangjing;Xing, Mingyan;Zhang, Yue;Deng, Jiangshan;Wang, Xiuzhe;Luo, Yan;Li, Jinbao;Zhao, Yuwu;Zhang, Haibing
Caspase-8 是死亡受体诱导的细胞凋亡的引发剂，也是 RIPK3-MLKL 依赖性坏死性凋亡的抑制剂。此外，caspase-8 与人类淋巴增殖、免疫缺陷和自身免疫等疾病有关。尽管自动切割对于 caspase-8 的激活是必不可少的，但其生理功能仍知之甚少。在这里，我们在自动切割位点敲入小鼠中生成了缺乏 E385 的 caspase-8 突变体 (Casp8ΔE385/ΔE385)。 Casp8ΔE385/ΔE385细胞预计能够抵抗Fas诱导的细胞凋亡，然而，Casp8ΔE385/ΔE385细胞可以通过减弱RIPK1裂解将TNF-α诱导的细胞凋亡转变为坏死性凋亡。更重要的是，CASP8（ΔE385）通过促进复合物II形成和RIPK1-RIPK3激活使细胞对RIPK3-MLKL依赖性坏死性凋亡敏感。值得注意的是，Casp8ΔE385/ΔE385Ripk3−/− 小鼠通过阻断细胞凋亡和坏死性凋亡，部分挽救了 Ripk1−/− 小鼠的围产期死亡。与出现自身免疫性淋巴细胞增殖综合征（ALPS）的 Casp8−/−Ripk3−/− 和 Casp8−/−Mlkl−/− 小鼠相比，Casp8ΔE385/ΔE385Ripk3−/− 和 Casp8ΔE385/ΔE385Mlkl−/− 小鼠均出现可移植性淋巴细胞减少症，这种现象可以通过 RIPK1 杂合性显着逆转，但不是由 RIPK1 激酶死亡突变引起的。总的来说，这些结果证明了 caspase-8 自动切割在调节坏死性凋亡和维持淋巴细胞稳态方面的作用，这一作用此前未被认识到。
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 (Casp8ΔE385/ΔE385). Casp8ΔE385/ΔE385 cells were expectedly resistant to Fas-induced apoptosis, however, Casp8ΔE385/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, Casp8ΔE385/ΔE385Ripk3−/− 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 Casp8ΔE385/ΔE385Ripk3−/− and Casp8ΔE385/ΔE385Mlkl−/− 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.
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影响因子：
16.6
作者：
Kang, Seokwon;Fernandes-Alnemri, Teresa;Rogers, Corey;Mayes, Lindsey;Wang, Ying;Dillon, Christopher;Roback, Linda;Kaiser, William;Oberst, Andrew;Sagara, Junji;Fitzgerald, Katherine A.;Green, Douglas R.;Zhang, Jianke;Mocarski, Edward S.;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
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影响因子：
4.8
作者：
Feng, Shanshan;Yang, Yonghui;Wu, Mian
通讯作者：
Wu, Mian
影响因子：
32.4
作者：
Alvarez-Diaz, Silvia;Dillon, Christopher P.;Lalaoui, Najoua;Tanzer, Maria C.;Rodriguez, Diego A.;Lin, Ann;Lebois, Marion;Hakem, Razq;Josefsson, Emma C.;O'Reilly, Lorraine A.;Silke, John;Alexander, Warren S.;Green, Douglas R.;Strasser, Andreas
通讯作者：
Strasser, Andreas
TBK1和IKKε预防TNF诱导的RIPK1磷酸化导致细胞死亡。
影响因子：
21.3
作者：
Lafont E;Draber P;Rieser E;Reichert M;Kupka S;de Miguel D;Draberova H;von Mässenhausen A;Bhamra A;Henderson S;Wojdyla K;Chalk A;Surinova S;Linkermann A;Walczak H
通讯作者：
Walczak H