Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury
Abstract Programmed necrosis involves three consecutive stages: initiation, propagation, and execution. The initiation of necrosis has been widely studied, but due to the diversity and pleiotropy of the initiating pathways, it is difficult to identify ideal targets for necrosis inhibition from upstr...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08255-w |
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| author | Chen Hu Jichuan Geng Peipei Shan Tongqing Zhang Zhuqing Zhang Xiaoyu Zhang Menghan Lin Xiaoxia Zhang Dong Chang Baokun He Deshui Jia Mary Zhang Chuangui Wang Shengping Zhang |
| author_facet | Chen Hu Jichuan Geng Peipei Shan Tongqing Zhang Zhuqing Zhang Xiaoyu Zhang Menghan Lin Xiaoxia Zhang Dong Chang Baokun He Deshui Jia Mary Zhang Chuangui Wang Shengping Zhang |
| author_sort | Chen Hu |
| collection | DOAJ |
| description | Abstract Programmed necrosis involves three consecutive stages: initiation, propagation, and execution. The initiation of necrosis has been widely studied, but due to the diversity and pleiotropy of the initiating pathways, it is difficult to identify ideal targets for necrosis inhibition from upstream necrosis pathways. Genetic evidence suggests that caspase-independent chromatinolysis, an execution process in multiple forms of necrosis, could be targeted to inhibit necrosis, but its regulatory mechanisms remain unclear. Previous studies suggest that the apoptosis-inducing factor AIF promotes chromatinolysis and caspase-independent necrosis, and its cytosol-to-nucleus translocation induces irreversible chromatinolysis. Here we report that AIF acetylation at lysine 295 is required for its cytosol-to-nucleus translocation and conduction of caspase-independent chromatinolysis upon necrotic stimuli, the SIRT1 deacetylase blocks necrotic chromatinolysis via deacetylating AIF, and pharmacological activation of SIRT1 inhibits AIF-dependent chromatinolysis and necrotic brain injury. Our results reveal a reversible blocking mechanism for AIF-dependent chromatinolysis and caspase-independent necrosis, supporting that targeting the late necrosis stage is a promising therapeutic strategy for treatment of necrosis-associated diseases. |
| format | Article |
| id | doaj-art-20f4b9e44110494f8d6eaefe9abf90aa |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-20f4b9e44110494f8d6eaefe9abf90aa2025-08-20T02:00:09ZengNature PortfolioCommunications Biology2399-36422025-05-018111710.1038/s42003-025-08255-wDeacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injuryChen Hu0Jichuan Geng1Peipei Shan2Tongqing Zhang3Zhuqing Zhang4Xiaoyu Zhang5Menghan Lin6Xiaoxia Zhang7Dong Chang8Baokun He9Deshui Jia10Mary Zhang11Chuangui Wang12Shengping Zhang13Biomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyInstitute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao UniversityBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyInstitute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese MedicineLaboratory of Cancer Genomics and Biology, Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyBiomedical Research Institute, School of Life Sciences and Medicine, Shandong University of TechnologyAbstract Programmed necrosis involves three consecutive stages: initiation, propagation, and execution. The initiation of necrosis has been widely studied, but due to the diversity and pleiotropy of the initiating pathways, it is difficult to identify ideal targets for necrosis inhibition from upstream necrosis pathways. Genetic evidence suggests that caspase-independent chromatinolysis, an execution process in multiple forms of necrosis, could be targeted to inhibit necrosis, but its regulatory mechanisms remain unclear. Previous studies suggest that the apoptosis-inducing factor AIF promotes chromatinolysis and caspase-independent necrosis, and its cytosol-to-nucleus translocation induces irreversible chromatinolysis. Here we report that AIF acetylation at lysine 295 is required for its cytosol-to-nucleus translocation and conduction of caspase-independent chromatinolysis upon necrotic stimuli, the SIRT1 deacetylase blocks necrotic chromatinolysis via deacetylating AIF, and pharmacological activation of SIRT1 inhibits AIF-dependent chromatinolysis and necrotic brain injury. Our results reveal a reversible blocking mechanism for AIF-dependent chromatinolysis and caspase-independent necrosis, supporting that targeting the late necrosis stage is a promising therapeutic strategy for treatment of necrosis-associated diseases.https://doi.org/10.1038/s42003-025-08255-w |
| spellingShingle | Chen Hu Jichuan Geng Peipei Shan Tongqing Zhang Zhuqing Zhang Xiaoyu Zhang Menghan Lin Xiaoxia Zhang Dong Chang Baokun He Deshui Jia Mary Zhang Chuangui Wang Shengping Zhang Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury Communications Biology |
| title | Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury |
| title_full | Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury |
| title_fullStr | Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury |
| title_full_unstemmed | Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury |
| title_short | Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury |
| title_sort | deacetylation of nuclear aif provides a braking mechanism for caspase independent chromatinolysis and necrotic brain injury |
| url | https://doi.org/10.1038/s42003-025-08255-w |
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