The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis
Abstract Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00622-3 |
| _version_ | 1797259485210738688 |
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| author | Shuolin Liu Yaguang Bi Tianting Han Yiran E. Li Qihang Wang Ne Natalie Wu Chenguo Xu Junbo Ge Ronggui Hu Yingmei Zhang |
| author_facet | Shuolin Liu Yaguang Bi Tianting Han Yiran E. Li Qihang Wang Ne Natalie Wu Chenguo Xu Junbo Ge Ronggui Hu Yingmei Zhang |
| author_sort | Shuolin Liu |
| collection | DOAJ |
| description | Abstract Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5–MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury. |
| first_indexed | 2024-03-07T15:20:45Z |
| format | Article |
| id | doaj.art-35a8717ca6e747e8af85a8312821f616 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-04-24T23:10:10Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-35a8717ca6e747e8af85a8312821f6162024-03-17T12:14:18ZengNature Publishing GroupCell Discovery2056-59682024-02-0110112310.1038/s41421-023-00622-3The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axisShuolin Liu0Yaguang Bi1Tianting Han2Yiran E. Li3Qihang Wang4Ne Natalie Wu5Chenguo Xu6Junbo Ge7Ronggui Hu8Yingmei Zhang9Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesCollege of Basic Medicine, Shanghai Medical College, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesCollege of Basic Medicine, Shanghai Medical College, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesCollege of Basic Medicine, Shanghai Medical College, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesCollege of Basic Medicine, Shanghai Medical College, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical SciencesAbstract Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5–MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.https://doi.org/10.1038/s41421-023-00622-3 |
| spellingShingle | Shuolin Liu Yaguang Bi Tianting Han Yiran E. Li Qihang Wang Ne Natalie Wu Chenguo Xu Junbo Ge Ronggui Hu Yingmei Zhang The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis Cell Discovery |
| title | The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis |
| title_full | The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis |
| title_fullStr | The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis |
| title_full_unstemmed | The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis |
| title_short | The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis |
| title_sort | e3 ubiquitin ligase march2 protects against myocardial ischemia reperfusion injury through inhibiting pyroptosis via negative regulation of pgam5 mavs nlrp3 axis |
| url | https://doi.org/10.1038/s41421-023-00622-3 |
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