VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Applied Mathematics, Computer Sciences, and Statistics, Ghent University, 9052 Ghent, Belgium.
Cell Rep. 2020 Feb 18;30(7):2237-2247.e6. doi: 10.1016/j.celrep.2020.01.028.
Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC.
炎症信号通路受到严格调控，以避免慢性炎症和疾病的发展。OTULIN 是一种去泛素化酶，通过切割线性泛素链组装复合物产生的线性泛素链来控制炎症。在这里，我们表明，在小鼠的肝实质细胞中敲除 OTULIN 会导致严重的肝病，其特征是肝脏炎症、肝细胞凋亡和代偿性肝细胞增殖，导致脂肪性肝炎、纤维化和肝细胞癌 (HCC)。Fas 相关死亡结构域 (FADD) 的基因缺失完全挽救了这种疾病，而激酶失活受体相互作用蛋白激酶 1 (RIPK1) 的敲入表达则显著保护了小鼠免于发生肝病，表明 OTULIN 缺陷型肝细胞的凋亡触发了该模型中的疾病发病机制。最后，我们证明了 I 型干扰素有助于肝特异性 OTULIN 缺陷型小鼠的疾病发展。我们的研究揭示了 OTULIN 在保护肝细胞免于死亡方面的至关重要性，从而防止慢性肝脏炎症和 HCC 的发展。
