USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells

作者全名："Zhao, Jinqiu; Bai, Jie; Peng, Fengling; Qiu, Chan; Li, Yongguo; Zhong, Li"

作者地址："[Zhao, Jinqiu; Bai, Jie; Peng, Fengling; Li, Yongguo] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing, Peoples R China; [Qiu, Chan; Zhong, Li] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China"

通信作者："Li, YG (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing, Peoples R China.; Zhong, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China."

来源：CELL DEATH & DISEASE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000915244700001

JCR分区：Q1

影响因子：8.1

年份：2023

卷号：14

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6-8 weeks old) were intraperitoneally injected with 10% CCl4 in olive oil (5 mu l/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 mu l/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-beta 1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis."

基金机构："National Natural Science Foundation of China [82000583]; Natural Science Foundation of Chongqing, China [cstc2020jcyj-msxmX0703]; National Natural Science Foundation of China [82100656]; China Postdoctoral Science Foundation [2022M710563]; Science and Technology Joint Medical Foundation of Chongqing, China [2020FYYX008]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (GrantNo.82000583), the Natural Science Foundation of Chongqing, China (Grant No.(cstc2020jcyj-msxmX0703), National Natural Science Foundation of China (Grant NO.82100656), China Postdoctoral Science Foundation(2022M710563), and Science and Technology Joint Medical Foundation of Chongqing, China (Grant NO. 2020FYYX008)."