Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis
Summary: Tank-binding kinase 1 (TBK1) is a critical signal transducer in the nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, essential for innate immunity. However, its negative regulation mechanisms remain unclear. This study demonstrates that TBK1 succinylation, regulate...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014116 |
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| author | Xuedi Zhang Chunxiu Ling Ziying Xiong Ting Gong Shuhua Luo Xiaolei Liu Lina Zhang Chaoxiong Liao Yue Lu Xiao Huang Wending Zhou Shuangnan Zhou Youtan Liu Jing Tang |
| author_facet | Xuedi Zhang Chunxiu Ling Ziying Xiong Ting Gong Shuhua Luo Xiaolei Liu Lina Zhang Chaoxiong Liao Yue Lu Xiao Huang Wending Zhou Shuangnan Zhou Youtan Liu Jing Tang |
| author_sort | Xuedi Zhang |
| collection | DOAJ |
| description | Summary: Tank-binding kinase 1 (TBK1) is a critical signal transducer in the nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, essential for innate immunity. However, its negative regulation mechanisms remain unclear. This study demonstrates that TBK1 succinylation, regulated by desuccinylase SIRT5, inhibits lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated NF-κB and IRF signaling activation. We identified three key succinylation sites on TBK1: K38, K154, and K692. In endotoxemia and sepsis models, reduced SIRT5 levels in macrophages increased TBK1 succinylation, inhibiting its binding to IRF3 and TRAF2 and suppressing the inflammatory response. In vivo, adoptive transfer of macrophages expressing the succinylation-resistant TBK1-2KR (K154/692R) mutant reversed the inflammatory cytokine suppression caused by SIRT5 deficiency, exacerbating sepsis-induced lung injury. These findings reveal a novel mechanism by which SIRT5 modulates TBK1 activity and macrophage-mediated inflammation during sepsis. |
| format | Article |
| id | doaj-art-31b79e1777df4fca8187d9ac2327b833 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-31b79e1777df4fca8187d9ac2327b8332024-12-15T06:15:26ZengElsevierCell Reports2211-12472024-12-014312115060Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsisXuedi Zhang0Chunxiu Ling1Ziying Xiong2Ting Gong3Shuhua Luo4Xiaolei Liu5Lina Zhang6Chaoxiong Liao7Yue Lu8Xiao Huang9Wending Zhou10Shuangnan Zhou11Youtan Liu12Jing Tang13The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China; Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, Guangdong 518110, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaDepartment of Anesthesiology, Shenzhen Hospital of Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, Guangdong 518110, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, ChinaSenior Department of Infectious Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; Corresponding authorDepartment of Anesthesiology, Shenzhen Hospital of Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, Guangdong 518110, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Corresponding authorThe Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China; Corresponding authorSummary: Tank-binding kinase 1 (TBK1) is a critical signal transducer in the nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, essential for innate immunity. However, its negative regulation mechanisms remain unclear. This study demonstrates that TBK1 succinylation, regulated by desuccinylase SIRT5, inhibits lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated NF-κB and IRF signaling activation. We identified three key succinylation sites on TBK1: K38, K154, and K692. In endotoxemia and sepsis models, reduced SIRT5 levels in macrophages increased TBK1 succinylation, inhibiting its binding to IRF3 and TRAF2 and suppressing the inflammatory response. In vivo, adoptive transfer of macrophages expressing the succinylation-resistant TBK1-2KR (K154/692R) mutant reversed the inflammatory cytokine suppression caused by SIRT5 deficiency, exacerbating sepsis-induced lung injury. These findings reveal a novel mechanism by which SIRT5 modulates TBK1 activity and macrophage-mediated inflammation during sepsis.http://www.sciencedirect.com/science/article/pii/S2211124724014116CP: Immunology |
| spellingShingle | Xuedi Zhang Chunxiu Ling Ziying Xiong Ting Gong Shuhua Luo Xiaolei Liu Lina Zhang Chaoxiong Liao Yue Lu Xiao Huang Wending Zhou Shuangnan Zhou Youtan Liu Jing Tang Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis Cell Reports CP: Immunology |
| title | Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis |
| title_full | Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis |
| title_fullStr | Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis |
| title_full_unstemmed | Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis |
| title_short | Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis |
| title_sort | desuccinylation of tbk1 by sirt5 regulates inflammatory response of macrophages in sepsis |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014116 |
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