Desuccinylation of TBK1 by SIRT5 regulates inflammatory response of macrophages in sepsis
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
Affiliations
Xuedi Zhang
The 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, China
Chunxiu Ling
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Ziying Xiong
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Ting Gong
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, China
Shuhua Luo
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Xiaolei Liu
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Lina Zhang
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Chaoxiong Liao
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Yue Lu
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Xiao Huang
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Wending Zhou
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China
Shuangnan Zhou
Senior Department of Infectious Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; Corresponding author
Youtan Liu
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, China; Corresponding author
Jing Tang
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China; Corresponding author
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.
