Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses
Abstract Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macro...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07362-0 |
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| author | Wenke Wang Boquan Wu Mingjun Hao Sichong Chen Ruiting Cong Wenjie Wu Pengbo Wang Qiaoyi Zhang Pengyu Jia Yuequn Song Bo Liu Siyao Qu Jian-Fei Pei Da Li Naijin Zhang |
| author_facet | Wenke Wang Boquan Wu Mingjun Hao Sichong Chen Ruiting Cong Wenjie Wu Pengbo Wang Qiaoyi Zhang Pengyu Jia Yuequn Song Bo Liu Siyao Qu Jian-Fei Pei Da Li Naijin Zhang |
| author_sort | Wenke Wang |
| collection | DOAJ |
| description | Abstract Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macrophages depended on the acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 acetylation restricted the release of pro-inflammatory factors. Mechanistically, we found a crucial AMPK-CLYBL acetylation positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation and CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as the bridge between AMPK phosphorylation and CLYBL acetylation, thereby regulating macrophage polarization and the release of pro-inflammatory cytokines. Furthermore, CLYBL hypoacetylation decreased monocyte infiltration, thereby alleviating cardiac remodeling. These findings suggest that the AMPK-CLYBL acetylation positive feedback loop serves as a metabolic switch driving inflammatory response and inhibiting CLYBL-K154 acetylation may offer a promising therapeutic strategy for inflammatory response-related disorders. |
| format | Article |
| id | doaj-art-a8195f9811fd4643855cbc5ab5b67ef6 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a8195f9811fd4643855cbc5ab5b67ef62025-01-26T12:54:50ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111210.1038/s41419-025-07362-0Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responsesWenke Wang0Boquan Wu1Mingjun Hao2Sichong Chen3Ruiting Cong4Wenjie Wu5Pengbo Wang6Qiaoyi Zhang7Pengyu Jia8Yuequn Song9Bo Liu10Siyao Qu11Jian-Fei Pei12Da Li13Naijin Zhang14Center of Reproductive Medicine, Shengjing Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityCenter of Reproductive Medicine, Shengjing Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityCenter of Reproductive Medicine, Shengjing Hospital of China Medical UniversityCenter of Reproductive Medicine, Shengjing Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Cardiology, The First Hospital of China Medical UniversityDepartment of Neurosurgery, the Fourth Affiliated Hospital of China Medical UniversityDepartment of Cardiac Surgery, The First Hospital of China Medical UniversityDepartment of Medical Genetics, China Medical UniversityDepartment of Medical Genetics, China Medical UniversityCenter of Reproductive Medicine, Shengjing Hospital of China Medical UniversityNHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health CommissionAbstract Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macrophages depended on the acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 acetylation restricted the release of pro-inflammatory factors. Mechanistically, we found a crucial AMPK-CLYBL acetylation positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation and CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as the bridge between AMPK phosphorylation and CLYBL acetylation, thereby regulating macrophage polarization and the release of pro-inflammatory cytokines. Furthermore, CLYBL hypoacetylation decreased monocyte infiltration, thereby alleviating cardiac remodeling. These findings suggest that the AMPK-CLYBL acetylation positive feedback loop serves as a metabolic switch driving inflammatory response and inhibiting CLYBL-K154 acetylation may offer a promising therapeutic strategy for inflammatory response-related disorders.https://doi.org/10.1038/s41419-025-07362-0 |
| spellingShingle | Wenke Wang Boquan Wu Mingjun Hao Sichong Chen Ruiting Cong Wenjie Wu Pengbo Wang Qiaoyi Zhang Pengyu Jia Yuequn Song Bo Liu Siyao Qu Jian-Fei Pei Da Li Naijin Zhang Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses Cell Death and Disease |
| title | Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses |
| title_full | Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses |
| title_fullStr | Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses |
| title_full_unstemmed | Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses |
| title_short | Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses |
| title_sort | positive feedback loop involving ampk and clybl acetylation links metabolic rewiring and inflammatory responses |
| url | https://doi.org/10.1038/s41419-025-07362-0 |
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