KDM4B enhances immune surveillance via demethylating cGAS
Abstract Cyclic GMP–AMP synthase (cGAS) serves as a crucial sentinel in innate immunity by sensing cytosolic DNA, yet the molecular mechanisms governing its activation remain incompletely understood. Here, we identify lysine demethylase 4B (KDM4B) as the specific demethylase that erases cGAS K350 me...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07792-w |
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| author | Qiao Peng Huimin Zhuo Minkang Wu Yun Hao Yiyi Zhang Yuying Zheng Lei Yu Lin Han Hui Ren Yingcong Wang Zhijie Gao Leilei Wu Qi Lin Chunhua Lu Jinghua Li Ping Wang Lan Fang Haihong Yu Meiling Lu |
| author_facet | Qiao Peng Huimin Zhuo Minkang Wu Yun Hao Yiyi Zhang Yuying Zheng Lei Yu Lin Han Hui Ren Yingcong Wang Zhijie Gao Leilei Wu Qi Lin Chunhua Lu Jinghua Li Ping Wang Lan Fang Haihong Yu Meiling Lu |
| author_sort | Qiao Peng |
| collection | DOAJ |
| description | Abstract Cyclic GMP–AMP synthase (cGAS) serves as a crucial sentinel in innate immunity by sensing cytosolic DNA, yet the molecular mechanisms governing its activation remain incompletely understood. Here, we identify lysine demethylase 4B (KDM4B) as the specific demethylase that erases cGAS K350 methylation, facilitating its chromatin release and subsequent activation. Genetic ablation of Kdm4b compromised both antiviral immunity against HSV-1 infection and antitumor responses, while also diminishing the efficacy of anti-PD-1 immunotherapy. Mechanistically, KDM4B-mediated cGAS demethylation proved crucial for its proper subcellular distribution and activation. In the context of autoimmune diseases, we found that targeting KDM4B–cGAS axis through either genetic approaches or pharmacological inhibition of KDM4B with JIB-04 effectively ameliorated disease manifestations in both Trex1-deficient mice and peripheral blood mononuclear cells from Aicardi-Goutieres syndrome (AGS) patients. Collectively, this study demonstrated that KDM4B functions as a specific demethylase for cGAS, controlling its chromatin dissociation and subsequent activation, thereby providing a therapeutic rationale for targeting cGAS methylation in human diseases. |
| format | Article |
| id | doaj-art-99f09422c63f4fd9bffbada6ab63019d |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-99f09422c63f4fd9bffbada6ab63019d2025-08-20T04:01:36ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111310.1038/s41419-025-07792-wKDM4B enhances immune surveillance via demethylating cGASQiao Peng0Huimin Zhuo1Minkang Wu2Yun Hao3Yiyi Zhang4Yuying Zheng5Lei Yu6Lin Han7Hui Ren8Yingcong Wang9Zhijie Gao10Leilei Wu11Qi Lin12Chunhua Lu13Jinghua Li14Ping Wang15Lan Fang16Haihong Yu17Meiling Lu18Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityDepartment of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityShanghai Tenth People’s Hospital, School of Medicine, Tongji UniversityAbstract Cyclic GMP–AMP synthase (cGAS) serves as a crucial sentinel in innate immunity by sensing cytosolic DNA, yet the molecular mechanisms governing its activation remain incompletely understood. Here, we identify lysine demethylase 4B (KDM4B) as the specific demethylase that erases cGAS K350 methylation, facilitating its chromatin release and subsequent activation. Genetic ablation of Kdm4b compromised both antiviral immunity against HSV-1 infection and antitumor responses, while also diminishing the efficacy of anti-PD-1 immunotherapy. Mechanistically, KDM4B-mediated cGAS demethylation proved crucial for its proper subcellular distribution and activation. In the context of autoimmune diseases, we found that targeting KDM4B–cGAS axis through either genetic approaches or pharmacological inhibition of KDM4B with JIB-04 effectively ameliorated disease manifestations in both Trex1-deficient mice and peripheral blood mononuclear cells from Aicardi-Goutieres syndrome (AGS) patients. Collectively, this study demonstrated that KDM4B functions as a specific demethylase for cGAS, controlling its chromatin dissociation and subsequent activation, thereby providing a therapeutic rationale for targeting cGAS methylation in human diseases.https://doi.org/10.1038/s41419-025-07792-w |
| spellingShingle | Qiao Peng Huimin Zhuo Minkang Wu Yun Hao Yiyi Zhang Yuying Zheng Lei Yu Lin Han Hui Ren Yingcong Wang Zhijie Gao Leilei Wu Qi Lin Chunhua Lu Jinghua Li Ping Wang Lan Fang Haihong Yu Meiling Lu KDM4B enhances immune surveillance via demethylating cGAS Cell Death and Disease |
| title | KDM4B enhances immune surveillance via demethylating cGAS |
| title_full | KDM4B enhances immune surveillance via demethylating cGAS |
| title_fullStr | KDM4B enhances immune surveillance via demethylating cGAS |
| title_full_unstemmed | KDM4B enhances immune surveillance via demethylating cGAS |
| title_short | KDM4B enhances immune surveillance via demethylating cGAS |
| title_sort | kdm4b enhances immune surveillance via demethylating cgas |
| url | https://doi.org/10.1038/s41419-025-07792-w |
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