BRISC inactivation alleviates alcohol-induced liver injury in mice
Abstract BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure,...
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-89796-2 |
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| author | Ting Wang Wen Zhang Xian Liu Kai Liu Guang-Ming Ren Shen-Si Xiang Yi-Qun Zhan Hui Chen Hui-Ying Gao Ke Zhao Miao Yu Chang-Yan Li Xiao-Ming Yang Rong-Hua Yin |
| author_facet | Ting Wang Wen Zhang Xian Liu Kai Liu Guang-Ming Ren Shen-Si Xiang Yi-Qun Zhan Hui Chen Hui-Ying Gao Ke Zhao Miao Yu Chang-Yan Li Xiao-Ming Yang Rong-Hua Yin |
| author_sort | Ting Wang |
| collection | DOAJ |
| description | Abstract BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure, while its functional contribution to alcoholic liver disease (ALD) is still unclear. In this study, we found that the expression of BRISC components was increased in liver tissues of alcoholic hepatitis (AH) animal models and patients with AH. Mice lacking either the scaffold subunit ABRO1 or the catalytic subunit BRCC3 showed attenuated liver steatosis, inflammation, and liver injury compared to control mice after chronic plus binge ethanol feeding. Moreover, pharmacological inhibition of BRISC activity by a BRISC inhibitor thiolutin potently protected mice from ALD development. Preliminary mechanistical studies showed that BRISC deficiency did not directly affect alcohol-induced hepatocyte injury or the translocation of LPS through the damaged gut mucosa after ethanol feeding, but prevented alcohol-induced NLRP3 inflammasome activation in liver. Collectively, our work revealed a previously unknown role of BRISC in ALD and suggested that BRISC may serve as a promising therapeutic target for ALD treatment. |
| format | Article |
| id | doaj-art-1e1f304f873a4fd18481cbe0ff67e978 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-1e1f304f873a4fd18481cbe0ff67e9782025-08-20T03:00:58ZengNature PortfolioScientific Reports2045-23222025-02-0115111210.1038/s41598-025-89796-2BRISC inactivation alleviates alcohol-induced liver injury in miceTing Wang0Wen Zhang1Xian Liu2Kai Liu3Guang-Ming Ren4Shen-Si Xiang5Yi-Qun Zhan6Hui Chen7Hui-Ying Gao8Ke Zhao9Miao Yu10Chang-Yan Li11Xiao-Ming Yang12Rong-Hua Yin13Faculty of Chemistry and Life Sciences, Beijing University of TechnologyTianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of CommerceInstitute of Health Service and Transfusion MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineFaculty of Chemistry and Life Sciences, Beijing University of TechnologyState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation MedicineAbstract BRCC3 isopeptidase complex (BRISC) is a JAMM subfamily deubiquitinase that has been revealed to be required for optional activation of NLRP3 inflammasome and TLR4/NF-κB signaling pathway. BRISC plays an important role in lipopolysaccharide (LPS)/D-galactosamine-induced acute liver failure, while its functional contribution to alcoholic liver disease (ALD) is still unclear. In this study, we found that the expression of BRISC components was increased in liver tissues of alcoholic hepatitis (AH) animal models and patients with AH. Mice lacking either the scaffold subunit ABRO1 or the catalytic subunit BRCC3 showed attenuated liver steatosis, inflammation, and liver injury compared to control mice after chronic plus binge ethanol feeding. Moreover, pharmacological inhibition of BRISC activity by a BRISC inhibitor thiolutin potently protected mice from ALD development. Preliminary mechanistical studies showed that BRISC deficiency did not directly affect alcohol-induced hepatocyte injury or the translocation of LPS through the damaged gut mucosa after ethanol feeding, but prevented alcohol-induced NLRP3 inflammasome activation in liver. Collectively, our work revealed a previously unknown role of BRISC in ALD and suggested that BRISC may serve as a promising therapeutic target for ALD treatment.https://doi.org/10.1038/s41598-025-89796-2Alcoholic liver diseaseBRISCThiolutinLiver steatosisInflammationNLRP3 inflammasome |
| spellingShingle | Ting Wang Wen Zhang Xian Liu Kai Liu Guang-Ming Ren Shen-Si Xiang Yi-Qun Zhan Hui Chen Hui-Ying Gao Ke Zhao Miao Yu Chang-Yan Li Xiao-Ming Yang Rong-Hua Yin BRISC inactivation alleviates alcohol-induced liver injury in mice Scientific Reports Alcoholic liver disease BRISC Thiolutin Liver steatosis Inflammation NLRP3 inflammasome |
| title | BRISC inactivation alleviates alcohol-induced liver injury in mice |
| title_full | BRISC inactivation alleviates alcohol-induced liver injury in mice |
| title_fullStr | BRISC inactivation alleviates alcohol-induced liver injury in mice |
| title_full_unstemmed | BRISC inactivation alleviates alcohol-induced liver injury in mice |
| title_short | BRISC inactivation alleviates alcohol-induced liver injury in mice |
| title_sort | brisc inactivation alleviates alcohol induced liver injury in mice |
| topic | Alcoholic liver disease BRISC Thiolutin Liver steatosis Inflammation NLRP3 inflammasome |
| url | https://doi.org/10.1038/s41598-025-89796-2 |
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