The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling
The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling
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DOI：
10.1016/j.jgg.2022.02.013
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发表时间：
2022-04-29
影响因子：
5.9
通讯作者：
Liang, Bin
中科院分区：
文献类型：
--
作者：
Zhu, Tingting;Zhang, Linqiang;Liang, Bin
肝纤维化是各类慢性肝病的关键转化阶段，也是可逆的病理过程。然而，肝纤维化的发病机制仍不清楚。在这里，我们报告钙结合蛋白 A11 (S100A11) 在 GSE 肝纤维化和树鼩肝蛋白质组学的综合数据中持续上调。 S100A11 还在小鼠、大鼠、树鼩和患有肝纤维化的人的肝纤维化中被实验激活。虽然S100A11在体内和体外的过度表达会加剧肝纤维化，但抑制S100A11可改善肝纤维化。从机制上讲，S100A11 通过调节 TGF-β 信号通路中 Smad3 的脱乙酰化来激活肝星状细胞 (HSC) 和纤维形成过程。 S100A11 与 SIRT6（Smad2/3 的脱乙酰酶）发生物理相互作用，可能竞争性抑制 SIRT6 和 Smad2/3 之间的相互作用。随后 Smad2/3 的释放和激活促进 HSC 的激活和纤维形成。此外，在临床患者中观察到血清中 S100A11 显着升高。我们的研究发现S100A11是肝纤维化中的一种新型促纤维化因子，它可能代表了治疗肝纤维化和纤维化相关肝脏疾病的潜在生物标志物和有前景的治疗靶点。版权所有(C)2022，中国科学院遗传与发育生物学研究所，中国遗传学会。由爱思唯尔有限公司和科学出版社出版。版权所有。
Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases. However, the pathogenesis of liver fibrosis still remains elusive. Here, we report that the calcium binding protein A11 (S100A11) is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics. S100A11 is also experimentally activated in liver fibrosis in mouse, rat, tree shrew, and human with liver fibrosis. While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis, the inhibition of S100A11 improves liver fibrosis. Mechanistically, S100A11 activates hepatic stellate cells (HSCs) and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-beta signaling pathway. S100A11 physically interacts with SIRT6, a deacetylase of Smad2/3, which may competitively inhibit the interaction between SIRT6 and Smad2/3. The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis. Additionally, a significant elevation of S100A11 in serum is observed in clinical patients. Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis, which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases. Copyright (C) 2022, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.