Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1.
Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1.
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Bcl-3通过调节RIP1去泛素化促进TNF诱导的肝细胞凋亡
DOI：
10.1038/s41418-021-00908-7
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发表时间：
2022-06
影响因子：
12.4
通讯作者：
Zhang, Xiaoren
中科院分区：
文献类型：
--
作者：
Hu, Yiming;Zhang, Haohao;Xie, Ningxia;Liu, Dandan;Jiang, Yuhang;Liu, Zhi;Ye, Deji;Liu, Sanhong;Chen, Xi;Li, Cuifeng;Wang, Qi;Huang, Xingxu;Liu, Yongzhong;Shi, Yufang;Zhang, Xiaoren
肿瘤坏死因子-α （Tumor necrosis factor-α， TNF）被认为是多种细胞（包括肝细胞）存活和凋亡的主要调节因子。tnf诱导的细胞凋亡失调与许多自身免疫性疾病和多种肝脏疾病有关。在这里，我们证明了IκB家族成员Bcl-3在调节tnf诱导的肝细胞死亡中的关键作用。具体来说，我们发现Bcl-3的存在促进了TNF诱导的肝脏细胞死亡，而Bcl-3缺乏保护小鼠免受TNF/D-GalN诱导的肝毒性和致死率。一致地，当TNF/CHX刺激时，bcl -3缺失的肝细胞对TNF诱导的凋亡的敏感性降低。体外实验结果表明，Bcl-3与去泛素酶CYLD相互作用，协同改变RIP1的泛素化状态，促进死亡诱导复合物II的形成。该复合物进一步激活caspase级联，诱导细胞凋亡。通过揭示Bcl-3在调节tnf诱导的肝细胞死亡中的新作用，本研究为tnf相关凋亡引起的肝脏疾病提供了潜在的治疗靶点。
Tumor necrosis factor-α (TNF) is described as a main regulator of cell survival and apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the caspase cascade to induce apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related apoptosis.
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影响因子：
32.4
作者：
Legler, DF;Micheau, O;Bron, C
通讯作者：
Bron, C
影响因子：
9
作者：
通讯作者：
--
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J
DOI：
10.1084/jem.20070318
发表时间：
2007-10-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hövelmeyer N;Wunderlich FT;Massoumi R;Jakobsen CG;Song J;Wörns MA;Merkwirth C;Kovalenko A;Aumailley M;Strand D;Brüning JC;Galle PR;Wallach D;Fässler R;Waisman A
通讯作者：
Waisman A