Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production
Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte....
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.745985/full |
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| author | Fangqiao Lv Tinghui Shao Yujia Xue Xiulian Miao Yan Guo Yutong Wang Yong Xu Yong Xu |
| author_facet | Fangqiao Lv Tinghui Shao Yujia Xue Xiulian Miao Yan Guo Yutong Wang Yong Xu Yong Xu |
| author_sort | Fangqiao Lv |
| collection | DOAJ |
| description | Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte. Here we report that BRG1 deletion led to simultaneous down-regulation in expression and phosphorylation of tank binding kinase 1 (TBK1) in vivo and in vitro. On the one hand, BRG1 interacted with AP-1 to bind to the TBK1 promoter and directly activated TBK1 transcription in hepatocytes. On the other hand, BRG1 interacted with Sp1 to activate the transcription of c-SRC, a tyrosine kinase essential for TBK1 phosphorylation. Over-expression of c-SRC and TBK1 corrected the deficiency in ROS production in BRG1-null hepatocytes whereas depletion of TBK1 or c-SRC attenuated ROS production. In conclusion, our data suggest that dual regulation of TBK1 activity, at the transcription level and the post-transcriptional level, by BRG1 may constitute an important mechanism underlying excessive ROS production in hepatocytes. |
| first_indexed | 2024-12-17T12:17:18Z |
| format | Article |
| id | doaj.art-c626ed0c7eb345d890fa926165d5367f |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T12:17:18Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-c626ed0c7eb345d890fa926165d5367f2022-12-21T21:49:07ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-10-01910.3389/fcell.2021.745985745985Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species ProductionFangqiao Lv0Tinghui Shao1Yujia Xue2Xiulian Miao3Yan Guo4Yutong Wang5Yong Xu6Yong Xu7Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaCollege of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, ChinaCollege of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, ChinaDepartment of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, School of Basic Medical Sciences, Capital Medical University, Beijing, ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaCollege of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, ChinaExcessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte. Here we report that BRG1 deletion led to simultaneous down-regulation in expression and phosphorylation of tank binding kinase 1 (TBK1) in vivo and in vitro. On the one hand, BRG1 interacted with AP-1 to bind to the TBK1 promoter and directly activated TBK1 transcription in hepatocytes. On the other hand, BRG1 interacted with Sp1 to activate the transcription of c-SRC, a tyrosine kinase essential for TBK1 phosphorylation. Over-expression of c-SRC and TBK1 corrected the deficiency in ROS production in BRG1-null hepatocytes whereas depletion of TBK1 or c-SRC attenuated ROS production. In conclusion, our data suggest that dual regulation of TBK1 activity, at the transcription level and the post-transcriptional level, by BRG1 may constitute an important mechanism underlying excessive ROS production in hepatocytes.https://www.frontiersin.org/articles/10.3389/fcell.2021.745985/fulltranscription regulationchromatin remodeling proteinkinasephosphorylationROShepatocyte |
| spellingShingle | Fangqiao Lv Tinghui Shao Yujia Xue Xiulian Miao Yan Guo Yutong Wang Yong Xu Yong Xu Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production Frontiers in Cell and Developmental Biology transcription regulation chromatin remodeling protein kinase phosphorylation ROS hepatocyte |
| title | Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production |
| title_full | Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production |
| title_fullStr | Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production |
| title_full_unstemmed | Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production |
| title_short | Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production |
| title_sort | dual regulation of tank binding kinase 1 by brg1 in hepatocytes contributes to reactive oxygen species production |
| topic | transcription regulation chromatin remodeling protein kinase phosphorylation ROS hepatocyte |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.745985/full |
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