Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease.
Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease.
复制标题
DOI：
10.1016/j.jhep.2015.07.034
复制
发表时间：
2015-12
影响因子：
25.7
通讯作者：
Mann DA
中科院分区：
文献类型：
--
作者：
Wilson CL;Murphy LB;Leslie J;Kendrick S;French J;Fox CR;Sheerin NS;Fisher A;Robinson JH;Tiniakos DG;Gray DA;Oakley F;Mann DA
泛素化是一种可逆的蛋白质修饰，参与定义细胞表型和行为的主要细胞过程。泛素修饰可被称为去泛素酶的一大类蛋白酶去除。去泛素酶在肝星状细胞 (HSC) 激活中的作用及其对纤维发生的贡献尚不清楚。我们发现去泛素酶泛素 C 末端水解酶 1 (UCHL1) 在 HSC 激活后被高度诱导，确定了其在激活的 HSC 中的功能及其作为纤维化治疗靶点的潜力。在第 0 天和第 10 天的 HSC 中测定去泛素酶表达。在人类 HSC 和酒精性肝病 (ALD) 患者肝脏中证实了 UCHL1 表达增加。使用药理学抑制剂 (LDN 57444) 在 CCl4 和胆管结扎损伤小鼠中研究了 UCHL1 在肝纤维化中的重要性。通过蛋白质印迹和 3H 胸苷掺入证实了 UCHL1 抑制对 HSC 增殖的影响。在此，我们报道了 UCHL1 的药理学抑制可阻止 CCl4 损伤小鼠中已形成纤维化的进展。 UCHL1 siRNA 敲低、LDN 57444 治疗或从 UCHL1–/– 小鼠中分离的 HSC 表现出对丝裂原、血小板衍生生长因子的增殖减弱。此外，我们观察到在 UCHL1 缺失的情况下细胞周期调节因子视网膜母细胞瘤蛋白 (Rb) 磷酸化的变化，凸显了增殖反应减少的潜在机制。 UCHL1 表达在 HSC 激活后高度上调，并参与 HSC 增殖的调节。这项研究强调了 UCHL1 药物靶向治疗慢性肝病的治疗机会。
Ubiquitination is a reversible protein modification involved in the major cellular processes that define cell phenotype and behaviour. Ubiquitin modifications are removed by a large family of proteases named deubiquitinases. The role of deubiquitinases in hepatic stellate cell (HSC) activation and their contribution to fibrogenesis are poorly defined. We have identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, determined its function in activated HSC and its potential as a therapeutic target for fibrosis. Deubiquitinase expression was determined in day 0 and day 10 HSC. Increased UCHL1 expression was confirmed in human HSC and in an alcoholic liver disease (ALD) patient liver. The importance of UCHL1 in hepatic fibrosis was investigated in CCl4 and bile duct ligation injured mice using a pharmacological inhibitor (LDN 57444). The effects of UCHL1 inhibition on HSC proliferation were confirmed by Western blot and 3H thymidine incorporation. Here we report that pharmacological inhibition of UCHL1 blocks progression of established fibrosis in CCl4 injured mice. UCHL1 siRNA knockdown, LDN 57444 treatment, or HSC isolated from UCHL1–/– mice show attenuated proliferation in response to the mitogen, platelet-derived growth factor. Additionally, we observed changes in the phosphorylation of the cell cycle regulator retinoblastoma protein (Rb) in the absence of UCHL1 highlighting a potential mechanism for the reduced proliferative response. UCHL1 expression is highly upregulated upon HSC activation and is involved in the regulation of HSC proliferation. This study highlights therapeutic opportunities for pharmacological targeting of UCHL1 in chronic liver disease.