USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2
Abstract Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin‐specific protease USP25 significantly aggravate ischemic stroke injury in m...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202301641 |
| _version_ | 1797663862722396160 |
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| author | Zhongding Li Baohua Liu Kate Lykke Lambertsen Bettina Hjelm Clausen Zhenhu Zhu Xue Du Yanqi Xu Frantz Rom Poulsen Bo Halle Christian Bonde Meng Chen Xue Wang Dirk Schlüter Jingyong Huang Ari Waisman Weihong Song Xu Wang |
| author_facet | Zhongding Li Baohua Liu Kate Lykke Lambertsen Bettina Hjelm Clausen Zhenhu Zhu Xue Du Yanqi Xu Frantz Rom Poulsen Bo Halle Christian Bonde Meng Chen Xue Wang Dirk Schlüter Jingyong Huang Ari Waisman Weihong Song Xu Wang |
| author_sort | Zhongding Li |
| collection | DOAJ |
| description | Abstract Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin‐specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke‐induced neuronal loss and neurological deficits by inhibiting microglia‐mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF‐κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63‐specific polyubiquitin chains from TAB2. AAV9‐mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke. |
| first_indexed | 2024-03-11T19:22:00Z |
| format | Article |
| id | doaj.art-4949d5f837264796a353fe045437bd86 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T19:22:00Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-4949d5f837264796a353fe045437bd862023-10-07T03:51:50ZengWileyAdvanced Science2198-38442023-10-011028n/an/a10.1002/advs.202301641USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2Zhongding Li0Baohua Liu1Kate Lykke Lambertsen2Bettina Hjelm Clausen3Zhenhu Zhu4Xue Du5Yanqi Xu6Frantz Rom Poulsen7Bo Halle8Christian Bonde9Meng Chen10Xue Wang11Dirk Schlüter12Jingyong Huang13Ari Waisman14Weihong Song15Xu Wang16Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaDepartment of Neurological Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325027 ChinaDepartment of Neurobiology Research Institute of Molecular Medicine University of Southern Denmark Odense C 5000 DenmarkDepartment of Neurobiology Research Institute of Molecular Medicine University of Southern Denmark Odense C 5000 DenmarkSchool of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaSchool of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaSchool of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaBRIDGE – Brain Research – Inter Disciplinary Guided Excellence Department of Clinical Research University of Southern Denmark Odense C 5000 DenmarkBRIDGE – Brain Research – Inter Disciplinary Guided Excellence Department of Clinical Research University of Southern Denmark Odense C 5000 DenmarkBRIDGE – Brain Research – Inter Disciplinary Guided Excellence Department of Clinical Research University of Southern Denmark Odense C 5000 DenmarkDepartment of Neurological Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325027 ChinaSchool of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaInstitute of Medical Microbiology and Hospital Epidemiology Hannover Medical School 30625 Hannover GermanyDepartment of Vascular Surgery The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325015 ChinaInstitute for Molecular Medicine Johannes Gutenberg University Mainz 55131 Mainz GermanyOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) School of Pharmaceutical Sciences Wenzhou Medical University Wenzhou 325035 ChinaAbstract Cerebral ischemic stroke is a leading cause of morbidity and mortality globally. However, the mechanisms underlying ischemic stroke injury remain poorly understood. Here, it is found that deficiency of the ubiquitin‐specific protease USP25 significantly aggravate ischemic stroke injury in mice. USP25 has no impact on neuronal death under hypoxic conditions, but reduced ischemic stroke‐induced neuronal loss and neurological deficits by inhibiting microglia‐mediated neuroinflammation. Mechanistically, USP25 restricts the activation of NF‐κB and MAPK signaling by regulating TAB2. As a deubiquitinating enzyme, USP25 removeds K63‐specific polyubiquitin chains from TAB2. AAV9‐mediated TAB2 knockdown ameliorates ischemic stroke injury and abolishes the effect of USP25 deletion. In both mouse and human brains, USP25 is markedly upregulated in microglia in the ischemic penumbra, implying a clinical relevance of USP25 in ischemic stroke. Collectively, USP25 is identified as a critical inhibitor of ischemic stroke injury and this data suggest USP25 may serve as a therapeutic target for ischemic stroke.https://doi.org/10.1002/advs.202301641cerebral ischemic strokemicroglianeuroinflammationubiquitinationUSP25 |
| spellingShingle | Zhongding Li Baohua Liu Kate Lykke Lambertsen Bettina Hjelm Clausen Zhenhu Zhu Xue Du Yanqi Xu Frantz Rom Poulsen Bo Halle Christian Bonde Meng Chen Xue Wang Dirk Schlüter Jingyong Huang Ari Waisman Weihong Song Xu Wang USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 Advanced Science cerebral ischemic stroke microglia neuroinflammation ubiquitination USP25 |
| title | USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 |
| title_full | USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 |
| title_fullStr | USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 |
| title_full_unstemmed | USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 |
| title_short | USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2 |
| title_sort | usp25 inhibits neuroinflammatory responses after cerebral ischemic stroke by deubiquitinating tab2 |
| topic | cerebral ischemic stroke microglia neuroinflammation ubiquitination USP25 |
| url | https://doi.org/10.1002/advs.202301641 |
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