DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production
Abstract Mitogen‐activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma‐related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellula...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-09-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202101957 |
| _version_ | 1819101115826831360 |
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| author | Zilong Li Qianwen Zhao Yunjie Lu Yangxi Zhang Luyang Li Min Li Xuemin Chen Donglin Sun Yunfei Duan Yong Xu |
| author_facet | Zilong Li Qianwen Zhao Yunjie Lu Yangxi Zhang Luyang Li Min Li Xuemin Chen Donglin Sun Yunfei Duan Yong Xu |
| author_sort | Zilong Li |
| collection | DOAJ |
| description | Abstract Mitogen‐activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma‐related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage‐induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38‐MAPK signaling complex to drive ROS production in an S‐nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4‐inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38‐MAPK signaling, and ameliorate liver injury by influencing DDIT4 S‐nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S‐nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription‐based signaling cascade that contributes to ROS production in liver injury. |
| first_indexed | 2024-12-22T01:13:33Z |
| format | Article |
| id | doaj.art-9f43c7f2259940df83797497bc991bb8 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-22T01:13:33Z |
| publishDate | 2021-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-9f43c7f2259940df83797497bc991bb82022-12-21T18:43:55ZengWileyAdvanced Science2198-38442021-09-01818n/an/a10.1002/advs.202101957DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species ProductionZilong Li0Qianwen Zhao1Yunjie Lu2Yangxi Zhang3Luyang Li4Min Li5Xuemin Chen6Donglin Sun7Yunfei Duan8Yong Xu9Department of Hepatobiliary and Pancreatic Surgery The First People's Hospital of Changzhou The Third Affiliated Hospital of Soochow University Changzhou 213000 ChinaState Key Laboratory of Natural Medicines Department of Pharmacology China Pharmaceutical University Nanjing ChinaDepartment of Hepatobiliary and Pancreatic Surgery The First People's Hospital of Changzhou The Third Affiliated Hospital of Soochow University Changzhou 213000 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Translational Medicine Nanjing Medical University Nanjing 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Translational Medicine Nanjing Medical University Nanjing 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Translational Medicine Nanjing Medical University Nanjing 211166 ChinaDepartment of Hepatobiliary and Pancreatic Surgery The First People's Hospital of Changzhou The Third Affiliated Hospital of Soochow University Changzhou 213000 ChinaDepartment of Hepatobiliary and Pancreatic Surgery The First People's Hospital of Changzhou The Third Affiliated Hospital of Soochow University Changzhou 213000 ChinaDepartment of Hepatobiliary and Pancreatic Surgery The First People's Hospital of Changzhou The Third Affiliated Hospital of Soochow University Changzhou 213000 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Translational Medicine Nanjing Medical University Nanjing 211166 ChinaAbstract Mitogen‐activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma‐related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage‐induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38‐MAPK signaling complex to drive ROS production in an S‐nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4‐inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38‐MAPK signaling, and ameliorate liver injury by influencing DDIT4 S‐nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S‐nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription‐based signaling cascade that contributes to ROS production in liver injury.https://doi.org/10.1002/advs.202101957liver injuryp38 signalingpost‐translational modificationreactive oxygen species (ROS)transcriptional regulation |
| spellingShingle | Zilong Li Qianwen Zhao Yunjie Lu Yangxi Zhang Luyang Li Min Li Xuemin Chen Donglin Sun Yunfei Duan Yong Xu DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production Advanced Science liver injury p38 signaling post‐translational modification reactive oxygen species (ROS) transcriptional regulation |
| title | DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production |
| title_full | DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production |
| title_fullStr | DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production |
| title_full_unstemmed | DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production |
| title_short | DDIT4 S‐Nitrosylation Aids p38‐MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production |
| title_sort | ddit4 s nitrosylation aids p38 mapk signaling complex assembly to promote hepatic reactive oxygen species production |
| topic | liver injury p38 signaling post‐translational modification reactive oxygen species (ROS) transcriptional regulation |
| url | https://doi.org/10.1002/advs.202101957 |
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