METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome
N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m6A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unkno...
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.897487/full |
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| author | Yi Chen Yi Chen Yuling Wu Linjie Zhu Caiyang Chen Saihong Xu Dan Tang Yingfu Jiao Weifeng Yu |
| author_facet | Yi Chen Yi Chen Yuling Wu Linjie Zhu Caiyang Chen Saihong Xu Dan Tang Yingfu Jiao Weifeng Yu |
| author_sort | Yi Chen |
| collection | DOAJ |
| description | N6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m6A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of m6A RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of m6A RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS in vivo and in vitro. Furthermore, we identified tripartite motif-containing (Trim)59 as a key m6A effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS via m6A modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury. |
| first_indexed | 2024-12-12T10:04:44Z |
| format | Article |
| id | doaj.art-d5d46c41902e4ce6ae7393c214e0a413 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T10:04:44Z |
| publishDate | 2022-05-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-d5d46c41902e4ce6ae7393c214e0a4132022-12-22T00:27:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.897487897487METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress SyndromeYi Chen0Yi Chen1Yuling Wu2Linjie Zhu3Caiyang Chen4Saihong Xu5Dan Tang6Yingfu Jiao7Weifeng Yu8Department of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaThe Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, Shanghai, ChinaN6-methyladenosine (m6A) RNA modification is a fundamental determinant of mRNA metabolism in eukaryotic cells and is involved in numerous physiological and pathological processes. However, the specific role of m6A modification in sepsis-induced acute respiratory distress syndrome(ARDS) remains unknown. Here, we show that the levels of m6A RNA were significantly decreased in septic lungs and that METTL3 was the main regulator involved in the absence of m6A RNA modification. Pulmonary endothelial barrier damage is a critical process in the pathogenesis of acute lung injury during sepsis. METTL3 regulated endothelial barrier dysfunction and inflammatory responses in sepsis-induced ARDS in vivo and in vitro. Furthermore, we identified tripartite motif-containing (Trim)59 as a key m6A effector and Trim59 deficiency exacerbated lung injury. Mechanistically, METTL3 inhibited endothelial injury in sepsis-induced ARDS through Trim59-associated NF-κB inactivation. Our findings revealed novel insights into epitranscriptional mechanisms in sepsis-induced ARDS via m6A modifications, which has important application value in the diagnosis, prognosis, and molecular-targeted therapy of sepsis-associated lung injury.https://www.frontiersin.org/articles/10.3389/fimmu.2022.897487/fullsepsisacute lung injuryendothelial barrierepigenetic regulationm6AMETTL3 |
| spellingShingle | Yi Chen Yi Chen Yuling Wu Linjie Zhu Caiyang Chen Saihong Xu Dan Tang Yingfu Jiao Weifeng Yu METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome Frontiers in Immunology sepsis acute lung injury endothelial barrier epigenetic regulation m6A METTL3 |
| title | METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome |
| title_full | METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome |
| title_fullStr | METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome |
| title_full_unstemmed | METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome |
| title_short | METTL3-Mediated N6-Methyladenosine Modification of Trim59 mRNA Protects Against Sepsis-Induced Acute Respiratory Distress Syndrome |
| title_sort | mettl3 mediated n6 methyladenosine modification of trim59 mrna protects against sepsis induced acute respiratory distress syndrome |
| topic | sepsis acute lung injury endothelial barrier epigenetic regulation m6A METTL3 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.897487/full |
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