Zhang Xuedi, Ling Chunxiu, Xiong Ziying, Gong Ting, Luo Shuhua, Liu Xiaolei, Zhang Lina, Liao Chaoxiong, Lu Yue, Huang Xiao, Zhou Wending, Zhou Shuangnan, Liu Youtan, Tang Jing
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.
The Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China; Guang Dong Medical University, Zhanjiang, Guangdong 524000, China.
Cell Rep. 2024 Dec 24;43(12):115060. doi: 10.1016/j.celrep.2024.115060. Epub 2024 Dec 13.
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.
Tank结合激酶1（TBK1）是核因子κB（NF-κB）和干扰素调节因子（IRF）通路中的关键信号转导分子，对固有免疫至关重要。然而，其负调控机制仍不清楚。本研究表明，由去琥珀酰化酶SIRT5调控的TBK1琥珀酰化抑制脂多糖（LPS）/Toll样受体4（TLR4）介导的NF-κB和IRF信号激活。我们在TBK1上鉴定出三个关键的琥珀酰化位点：K38、K154和K692。在内毒素血症和脓毒症模型中，巨噬细胞中SIRT5水平降低会增加TBK1的琥珀酰化，抑制其与IRF3和TRAF2的结合，并抑制炎症反应。在体内，过继转移表达抗琥珀酰化TBK1-2KR（K154/692R）突变体的巨噬细胞可逆转由SIRT5缺乏引起的炎症细胞因子抑制，加重脓毒症诱导的肺损伤。这些发现揭示了一种新的机制，即SIRT5在脓毒症期间调节TBK1活性和巨噬细胞介导的炎症。
