Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke
Abstract As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2)...
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Springer Nature
2025-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00206-6 |
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| author | Fuqi Mei Deyu Deng Zijun Cao Liyan Lou Kangmin Chen Minjie Hu Zhenhu Zhu Jiangyun Shen Jianzhao Zhang Jie Liang Jingyong Huang Min Bao Ari Waisman Xu Wang |
| author_facet | Fuqi Mei Deyu Deng Zijun Cao Liyan Lou Kangmin Chen Minjie Hu Zhenhu Zhu Jiangyun Shen Jianzhao Zhang Jie Liang Jingyong Huang Min Bao Ari Waisman Xu Wang |
| author_sort | Fuqi Mei |
| collection | DOAJ |
| description | Abstract As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction in neuronal loss, glial activation, and neuroinflammation. OTUB2 was predominantly expressed in neurons and its deletion decreased receptor-interacting protein kinase 3 (RIPK3)-mediated neuronal necroptosis. Moreover, OTUB2 increased RIPK3 protein abundance by inhibiting the proteasomal degradation of RIPK3. Mechanistically, OTUB2 removed K48-linked polyubiquitin chains from RIPK3 through its active site C51. Importantly, pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and reduced oxygen-glucose deprivation-induced neuronal death in human brain organoids. These results demonstrate that OTUB2 critically regulates ischemic stroke injury by potentiating neuronal necroptosis, suggesting that OTUB2 inhibition may become a potential therapeutic approach for treating ischemic stroke. |
| format | Article |
| id | doaj-art-4231de83bdfd4aaa9a33ce95612fda7a |
| institution | OA Journals |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-4231de83bdfd4aaa9a33ce95612fda7a2025-08-20T02:28:04ZengSpringer NatureEMBO Molecular Medicine1757-46842025-02-0117467969510.1038/s44321-025-00206-6Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic strokeFuqi Mei0Deyu Deng1Zijun Cao2Liyan Lou3Kangmin Chen4Minjie Hu5Zhenhu Zhu6Jiangyun Shen7Jianzhao Zhang8Jie Liang9Jingyong Huang10Min Bao11Ari Waisman12Xu Wang13School of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health)Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health)Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health)School of Pharmaceutical Sciences, Wenzhou Medical UniversityDepartment of Rehabilitation, Central Hospital of Jinhua CityDepartment of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityOujiang Laboratory, The First Affiliated Hospital of Wenzhou Medical UniversityInstitute for Molecular Medicine, Johannes Gutenberg University MainzSchool of Pharmaceutical Sciences, Wenzhou Medical UniversityAbstract As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction in neuronal loss, glial activation, and neuroinflammation. OTUB2 was predominantly expressed in neurons and its deletion decreased receptor-interacting protein kinase 3 (RIPK3)-mediated neuronal necroptosis. Moreover, OTUB2 increased RIPK3 protein abundance by inhibiting the proteasomal degradation of RIPK3. Mechanistically, OTUB2 removed K48-linked polyubiquitin chains from RIPK3 through its active site C51. Importantly, pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and reduced oxygen-glucose deprivation-induced neuronal death in human brain organoids. These results demonstrate that OTUB2 critically regulates ischemic stroke injury by potentiating neuronal necroptosis, suggesting that OTUB2 inhibition may become a potential therapeutic approach for treating ischemic stroke.https://doi.org/10.1038/s44321-025-00206-6Ischemic StrokeNecroptosisUbiquitinationOTUB2RIPK3 |
| spellingShingle | Fuqi Mei Deyu Deng Zijun Cao Liyan Lou Kangmin Chen Minjie Hu Zhenhu Zhu Jiangyun Shen Jianzhao Zhang Jie Liang Jingyong Huang Min Bao Ari Waisman Xu Wang Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke EMBO Molecular Medicine Ischemic Stroke Necroptosis Ubiquitination OTUB2 RIPK3 |
| title | Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke |
| title_full | Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke |
| title_fullStr | Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke |
| title_full_unstemmed | Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke |
| title_short | Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke |
| title_sort | deubiquitination of ripk3 by otub2 potentiates neuronal necroptosis after ischemic stroke |
| topic | Ischemic Stroke Necroptosis Ubiquitination OTUB2 RIPK3 |
| url | https://doi.org/10.1038/s44321-025-00206-6 |
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