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Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-06 , DOI: 10.1038/s41419-019-2209-6 Jianye Wang 1 , Bian Hu 2 , Zhicong Zhao 1 , Haiyan Zhang 3 , He Zhang 1, 4 , Zhenjun Zhao 1 , Xiong Ma 5 , Bin Shen 6 , Beicheng Sun 7 , Xingxu Huang 2 , Jiajie Hou 3, 8 , Qiang Xia 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-06 , DOI: 10.1038/s41419-019-2209-6 Jianye Wang 1 , Bian Hu 2 , Zhicong Zhao 1 , Haiyan Zhang 3 , He Zhang 1, 4 , Zhenjun Zhao 1 , Xiong Ma 5 , Bin Shen 6 , Beicheng Sun 7 , Xingxu Huang 2 , Jiajie Hou 3, 8 , Qiang Xia 1
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Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an antiapoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.
中文翻译：
细胞内XBP1-IL-24轴可消除肝脏中未展开的细胞毒性蛋白反应。
内质网（ER）应激相关的细胞死亡在各种肝脏疾病中普遍存在。但是，尚不清楚肝细胞如何在未解决的压力下生存的决定性机制。先前发现白介素24（IL-24）促进内质网应激介导的细胞死亡，但其在肝脏中的表达和功能仍然难以捉摸。在这里，我们确定了IL-24的抗凋亡作用，它以X-box结合蛋白1（XBP1）依赖性方式在ER应激的肝细胞中短暂蓄积。IL-24的破坏增加了CCL4或APAP攻击的小鼠肝脏或Tm处理的肝细胞中的细胞死亡。相反，在没有IL-24的情况下，对真核生物起始因子2α（eIF2α）的药物阻断或C / EBP同源蛋白的遗传切除（CHOP）恢复了肝细胞功能。在临床环境中 急性肝功能衰竭患者表现出肝脏IL-24表达的大幅降低，这与疾病的进展有关。总之，内在的肝细胞IL-24通过限制eIF2α-CHOP途径介导的应激信号来维持ER稳态，该信号可能被用作肝损伤患者的预后或治疗干预的生物指标。
更新日期：2020-01-06
中文翻译：
细胞内XBP1-IL-24轴可消除肝脏中未展开的细胞毒性蛋白反应。
内质网（ER）应激相关的细胞死亡在各种肝脏疾病中普遍存在。但是，尚不清楚肝细胞如何在未解决的压力下生存的决定性机制。先前发现白介素24（IL-24）促进内质网应激介导的细胞死亡，但其在肝脏中的表达和功能仍然难以捉摸。在这里，我们确定了IL-24的抗凋亡作用，它以X-box结合蛋白1（XBP1）依赖性方式在ER应激的肝细胞中短暂蓄积。IL-24的破坏增加了CCL4或APAP攻击的小鼠肝脏或Tm处理的肝细胞中的细胞死亡。相反，在没有IL-24的情况下，对真核生物起始因子2α（eIF2α）的药物阻断或C / EBP同源蛋白的遗传切除（CHOP）恢复了肝细胞功能。在临床环境中 急性肝功能衰竭患者表现出肝脏IL-24表达的大幅降低，这与疾病的进展有关。总之，内在的肝细胞IL-24通过限制eIF2α-CHOP途径介导的应激信号来维持ER稳态，该信号可能被用作肝损伤患者的预后或治疗干预的生物指标。
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