c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities.
c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities.
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c-Jun N 末端激酶通过其激酶依赖性和独立性活性来差异调节 TNF 和 TLR 介导的坏死性凋亡。
DOI：
10.1038/s41419-018-1189-2
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发表时间：
2018-11-15
影响因子：
9
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Cao M;Chen F;Xie N;Cao MY;Chen P;Lou Q;Zhao Y;He C;Zhang S;Song X;Sun Y;Zhu W;Mou L;Luan S;Gao H
肿瘤坏死因子 (TNF) 和 Toll 样受体 (TLR)3/TLR4 激活通过包含受体相互作用蛋白激酶 1 (RIPK1)、RIPK3 和假激酶混合谱系激酶结构域 (MLKL) 的下游信号复合物触发坏死性细胞死亡。然而，坏死性凋亡信号通路的调控研究却少之又少。在这里，我们发现 c-Jun N 末端激酶（JNK1 和 JNK2）在调节 TNF 和 TLR 介导的坏死性凋亡中表现出激酶依赖性和独立性功能。我们发现 RIPK1 和 RIPK3 促进巨噬细胞中不依赖于细胞死亡的 JNK 激活，从而有助于促炎细胞因子的产生。同时，阻断 JNK 的激酶活性可显着减少 TNF 和 TLR 诱导的坏死性细胞死亡。一致地，抑制 JNK 活性可以保护小鼠免受 TNF 诱导的死亡和金黄色葡萄球菌介导的肺损伤。然而，使用 siRNA 消耗 JNK 蛋白会使巨噬细胞对 LPS 或 Poly I:C 引发的坏死性凋亡敏感，但仍能抑制 TNF 诱导的坏死性凋亡。机制研究表明，RIPK1 将 JNK 募集到坏死体复合物中，并且它们的激酶活性是坏死体形成以及 TNF 和 TLR 诱导的坏死性凋亡中 MLKL 磷酸化所必需的。 JNK蛋白的缺失始终抑制TNF触发的坏死性凋亡中MLKL的磷酸化和坏死体形成，但通过促进TRIF的寡聚而差异性地促进poly I:C触发的坏死性凋亡中MLKL的磷酸化和坏死体形成。总之，我们的研究结果定义了 JNK 在通过其激酶或支架活性调节 TNF 和 TLR 介导的坏死性凋亡中的不同作用。
Tumor necrosis factor (TNF) and Toll-like receptor (TLR)3/TLR4 activation trigger necroptotic cell death through downstream signaling complex containing receptor-interacting protein kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase-domain-like (MLKL). However, the regulation of necroptotic signaling pathway is far less investigated. Here we showed that c-Jun N-terminal kinases (JNK1 and JNK2) displayed kinase-dependent and -independent functions in regulating TNF- and TLRs-mediated necroptosis. We found that RIPK1 and RIPK3 promoted cell-death-independent JNK activation in macrophages, which contributed to pro-inflammatory cytokines production. Meanwhile, blocking the kinase activity of JNK dramatically reduced TNF and TLRs-induced necroptotic cell death. Consistently, inhibition of JNK activity protected mice from TNF-induced death and Staphylococcus aureus-mediated lung damage. However, depletion of JNK protein using siRNA sensitized macrophages to necroptosis that was triggered by LPS or poly I:C but still inhibited TNF-induced necroptosis. Mechanistic studies revealed that RIPK1 recruited JNK to the necrosome complex and their kinase activity was required for necrosome formation and the phosphorylation of MLKL in TNF- and TLRs-induced necroptosis. Loss of JNK protein consistently suppressed the phosphorylation of MLKL and necrosome formation in TNF-triggered necroptosis, but differentially promoted the phosphorylation of MLKL and necrosome formation in poly I:C-triggered necroptosis by promoting the oligomeration of TRIF. In conclusion, our findings define a differential role for JNK in regulating TNF- and TLRs-mediated necroptosis by their kinase or scaffolding activities.
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影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK
影响因子：
64.8
作者：
Dannappel M;Vlantis K;Kumari S;Polykratis A;Kim C;Wachsmuth L;Eftychi C;Lin J;Corona T;Hermance N;Zelic M;Kirsch P;Basic M;Bleich A;Kelliher M;Pasparakis M
通讯作者：
Pasparakis M