USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells
Abstract 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. Howeve...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05527-9 |
| _version_ | 1797945659968454656 |
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| author | Jinqiu Zhao Jie Bai Fengling Peng Chan Qiu Yongguo Li Li Zhong |
| author_facet | Jinqiu Zhao Jie Bai Fengling Peng Chan Qiu Yongguo Li Li Zhong |
| author_sort | Jinqiu Zhao |
| collection | DOAJ |
| description | Abstract 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 μl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 μl/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-β1, 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. |
| first_indexed | 2024-04-10T20:58:37Z |
| format | Article |
| id | doaj.art-34ff8ff5cfcf4ab6b756bdd0c28ad8cc |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T20:58:37Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-34ff8ff5cfcf4ab6b756bdd0c28ad8cc2023-01-22T12:26:40ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111010.1038/s41419-022-05527-9USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cellsJinqiu Zhao0Jie Bai1Fengling Peng2Chan Qiu3Yongguo Li4Li Zhong5Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical UniversityAbstract 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 μl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 μl/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-β1, 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.https://doi.org/10.1038/s41419-022-05527-9 |
| spellingShingle | Jinqiu Zhao Jie Bai Fengling Peng Chan Qiu Yongguo Li Li Zhong USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells Cell Death and Disease |
| title | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| title_full | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| title_fullStr | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| title_full_unstemmed | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| title_short | USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| title_sort | usp9x mediated nrp1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells |
| url | https://doi.org/10.1038/s41419-022-05527-9 |
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