The Linear ubiquitin chain assembly complex acts as a liver tumor suppressor and inhibits hepatocyte apoptosis and hepatitis.
The Linear ubiquitin chain assembly complex acts as a liver tumor suppressor and inhibits hepatocyte apoptosis and hepatitis.
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DOI：
10.1002/hep.29074
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Walczak H
中科院分区：
文献类型：
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作者：
Shimizu Y;Peltzer N;Sevko A;Lafont E;Sarr A;Draberova H;Walczak H
线性泛素化是一种关键的翻译后修饰，调节免疫信号传导和细胞死亡途径，特别是肿瘤坏死因子受体1（TNFR 1）信号传导。迄今为止，唯一已知的能够在天然条件下形成线性泛素链的酶复合物是线性泛素链组装复合物，其催化核心组分是血红素氧化铁调节蛋白2泛素连接酶1相互作用蛋白（HOIP）。为了了解维持肝脏稳态的潜在机制和线性泛素化在肝实质细胞中的作用，我们研究了HOIP在肝实质中的生理作用。为此，我们通过将Hoip‐floxed小鼠与白蛋白-Cre小鼠杂交，创建了肝实质细胞特异性HOIP缺失的小鼠（HoipΔhep小鼠）。肝实质细胞中HOIP缺乏在18个月龄时触发肿瘤发生，随后在出生后第一个月内发生自发性肝细胞凋亡和肝脏炎症。与炎症的出现一致，HoipΔhep小鼠显示出增强的肝再生和DNA损伤。此外，与细胞凋亡增加一致，HOIP缺陷肝细胞表现出caspase活化增强和内源性形成激活caspase-8的死亡诱导信号复合物。出乎意料的是，加剧的半胱天冬酶激活和细胞凋亡不依赖于TNFR 1，而随后的肝脏炎症和肿瘤发生是由TNFR 1信号促进的。结论：线性泛素链组装复合物在肝脏中充当先前未描述的肿瘤抑制因子，抑制肝细胞中的TNFR 1非依赖性凋亡，在其缺失的情况下，其是TNFR 1介导的炎症的原因，导致肝癌发生。（肝脏病学2017;65：1963 - 1978）。
Linear ubiquitination is a key posttranslational modification that regulates immune signaling and cell death pathways, notably tumor necrosis factor receptor 1 (TNFR1) signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex, of which the catalytic core component is heme‐oxidized iron regulatory protein 2 ubiquitin ligase‐1–interacting protein (HOIP). To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma. To do so, we created mice harboring liver parenchymal cell–specific deletion of HOIP (HoipΔhep mice) by crossing Hoip‐floxed mice with albumin–Cre mice. HOIP deficiency in liver parenchymal cells triggered tumorigenesis at 18 months of age preceded by spontaneous hepatocyte apoptosis and liver inflammation within the first month of life. In line with the emergence of inflammation, HoipΔhep mice displayed enhanced liver regeneration and DNA damage. In addition, consistent with increased apoptosis, HOIP‐deficient hepatocytes showed enhanced caspase activation and endogenous formation of a death‐inducing signaling complex which activated caspase‐8. Unexpectedly, exacerbated caspase activation and apoptosis were not dependent on TNFR1, whereas ensuing liver inflammation and tumorigenesis were promoted by TNFR1 signaling. Conclusion: The linear ubiquitin chain assembly complex serves as a previously undescribed tumor suppressor in the liver, restraining TNFR1‐independent apoptosis in hepatocytes which, in its absence, is causative of TNFR1‐mediated inflammation, resulting in hepatocarcinogenesis. (Hepatology 2017;65:1963‐1978).