Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7

Prominin-1 (PROM1), also known as CD133, is known to be expressed in hepatic progenitor cells (HPCs) and cholangiocytes of fibrotic liver. In this study, we show that PROM1 was upregulated in the plasma membranes of fibrotic hepatocytes. The hepatocellular expression of PROM1 was also demonstrated in the mice (Prom1CreER; R26TdTom) where cells express TdTom under the control of Prom1 promoter. To understand the role of hepatocellular PROM1 on liver fibrosis, global and liver- and cholangiocyte-specific Prom1-deficient mice were analyzed after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment. BDL- and CCl4-induced liver fibrosis was aggravated with increased phosphorylation of SMAD2/3 and decreased level of SMAD7 by global or liver-specific Prom1 deficiency but not by cholangiocyte-specific Prom1 deficiency. Indeed, PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated...Prominin-1（PROM1，亦称CD133）已知可在纤维化肝脏的肝祖细胞（hepatic progenitor cells, HPCs）与胆管上皮细胞中表达。本研究证实，PROM1在纤维化肝细胞的质膜中表达上调。我们还在Prom1CreER; R26TdTom小鼠模型中验证了PROM1的肝细胞表达：该模型中细胞可在Prom1启动子的调控下表达TdTom荧光蛋白。为探究肝细胞PROM1在肝纤维化进程中的作用，我们对胆管结扎（bile duct ligation, BDL）及四氯化碳（carbon tetrachloride, CCl4）造模后的全身性、肝脏特异性及胆管上皮细胞特异性Prom1敲除小鼠开展了分析。结果显示，全身性或肝脏特异性Prom1敲除可通过增强SMAD2/3磷酸化水平并降低SMAD7表达量，加剧BDL及CCl4诱导的肝纤维化，而胆管上皮细胞特异性Prom1敲除则无此调控效应。进一步机制实验证实，PROM1可通过干扰SMAD7与SMURF2的分子结合，阻断SMURF2介导的SMAD7泛素化与降解。本研究还证实……