TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury
Abstract Spinal cord injury (SCI) is a severe injury to the central nervous system, and its treatment is always a major medical challenge. Proinflammatory cell death is considered an important factor affecting neuroinflammation and the prognosis after injury. PANoptosis, a newly discovered type of p...
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Wiley
2024-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407132 |
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| author | Junsheng Lou Yiting Mao Wu Jiang Honghao Shen Yunpeng Fan Qing Yu Conghui Zhou Ziyao Wei Kailiang Zhou Mengran Jin Junsong Wu |
| author_facet | Junsheng Lou Yiting Mao Wu Jiang Honghao Shen Yunpeng Fan Qing Yu Conghui Zhou Ziyao Wei Kailiang Zhou Mengran Jin Junsong Wu |
| author_sort | Junsheng Lou |
| collection | DOAJ |
| description | Abstract Spinal cord injury (SCI) is a severe injury to the central nervous system, and its treatment is always a major medical challenge. Proinflammatory cell death is considered an important factor affecting neuroinflammation and the prognosis after injury. PANoptosis, a newly discovered type of proinflammatory cell death, regulates the activation of executioner molecules of apoptosis, pyroptosis and necroptosis through the PANoptosome, providing a new target for therapeutic intervention after SCI. However, its role and regulatory mechanism in SCI are not yet elucidated. Here, based on proteomic data, YBX1 expression is significantly increased in neurons after SCI. Guided by RIP‐seq, subsequent experiments reveal that YBX1 promotes ZBP1 expression by stabilizing the Zbp1 mRNA, thereby aggravating ZBP1‐mediated PANoptosis. Furthermore, the E3 ubiquitin ligase TRIM56 is identified as an endogenous inhibitor of YBX1 via molecular docking and IP/MS analysis. Mechanistically, TRIM56 bound to YBX1 and promoted its ubiquitination, thereby accelerating its degradation. Taken together, these findings reveal a novel function of YBX1 in regulating ZBP1‐mediated PANoptosis in the pathogenesis of SCI and verified that TRIM56 functions as an endogenous inhibitor to promote the ubiquitin‐proteasomal degradation of YBX1, providing new insights into SCI treatment strategies. |
| format | Article |
| id | doaj-art-aa4c5459346e41fe8fc8e3533e261fc7 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-aa4c5459346e41fe8fc8e3533e261fc72025-08-20T01:51:14ZengWileyAdvanced Science2198-38442024-11-011142n/an/a10.1002/advs.202407132TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord InjuryJunsheng Lou0Yiting Mao1Wu Jiang2Honghao Shen3Yunpeng Fan4Qing Yu5Conghui Zhou6Ziyao Wei7Kailiang Zhou8Mengran Jin9Junsong Wu10Department of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaObstetrics and Gynecology Hospital Institute of Reproduction and Development Fudan University Shanghai 200090 ChinaDepartment of Orthopeadics Affiliated Hangzhou First People's Hospital School of Medicine Westlake University No. 261 Huansha Road Hangzhou 310006 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaDepartment of Critical Care Medicine the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaDepartment of Orthopeadics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325027 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaDepartment of Orthopedic Surgery The First Affiliated Hospital Zhejiang University School of Medicine No. 79 Qingchun Road Hangzhou 310003 ChinaAbstract Spinal cord injury (SCI) is a severe injury to the central nervous system, and its treatment is always a major medical challenge. Proinflammatory cell death is considered an important factor affecting neuroinflammation and the prognosis after injury. PANoptosis, a newly discovered type of proinflammatory cell death, regulates the activation of executioner molecules of apoptosis, pyroptosis and necroptosis through the PANoptosome, providing a new target for therapeutic intervention after SCI. However, its role and regulatory mechanism in SCI are not yet elucidated. Here, based on proteomic data, YBX1 expression is significantly increased in neurons after SCI. Guided by RIP‐seq, subsequent experiments reveal that YBX1 promotes ZBP1 expression by stabilizing the Zbp1 mRNA, thereby aggravating ZBP1‐mediated PANoptosis. Furthermore, the E3 ubiquitin ligase TRIM56 is identified as an endogenous inhibitor of YBX1 via molecular docking and IP/MS analysis. Mechanistically, TRIM56 bound to YBX1 and promoted its ubiquitination, thereby accelerating its degradation. Taken together, these findings reveal a novel function of YBX1 in regulating ZBP1‐mediated PANoptosis in the pathogenesis of SCI and verified that TRIM56 functions as an endogenous inhibitor to promote the ubiquitin‐proteasomal degradation of YBX1, providing new insights into SCI treatment strategies.https://doi.org/10.1002/advs.202407132PANoptosisspinal cord injuryTRIM56YBX1ZBP1 |
| spellingShingle | Junsheng Lou Yiting Mao Wu Jiang Honghao Shen Yunpeng Fan Qing Yu Conghui Zhou Ziyao Wei Kailiang Zhou Mengran Jin Junsong Wu TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury Advanced Science PANoptosis spinal cord injury TRIM56 YBX1 ZBP1 |
| title | TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury |
| title_full | TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury |
| title_fullStr | TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury |
| title_full_unstemmed | TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury |
| title_short | TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1‐Mediated Neuronal PANoptosis in Spinal Cord Injury |
| title_sort | trim56 modulates ybx1 degradation to ameliorate zbp1 mediated neuronal panoptosis in spinal cord injury |
| topic | PANoptosis spinal cord injury TRIM56 YBX1 ZBP1 |
| url | https://doi.org/10.1002/advs.202407132 |
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