Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis

Dongdong Wang, Yanxia Li, Hao Yang, Xiaoqi Shen, Xiaolin Shi, Chenyu Li, Yongjing Zhang, Xiaoyu Liu, Bin Jiang, Xudong Zhu, Hanwen Zhang, Xiaoyu Li, Hui Bai, Qing Yang, Wei Gao, Fang Bai, Yong Ji, Qi Chen () and Jingjing Ben ()
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Dongdong Wang: Nanjing Medical University
Yanxia Li: Nanjing Medical University
Hao Yang: ShanghaiTech University
Xiaoqi Shen: Nanjing Medical University
Xiaolin Shi: Nanjing Medical University
Chenyu Li: Nanjing Medical University
Yongjing Zhang: Nanjing Medical University
Xiaoyu Liu: Nanjing Medical University
Bin Jiang: Nanjing Medical University
Xudong Zhu: Nanjing Medical University
Hanwen Zhang: Nanjing Medical University
Xiaoyu Li: Nanjing Medical University
Hui Bai: Nanjing Medical University
Qing Yang: Nanjing Medical University
Wei Gao: Nanjing Medical University
Fang Bai: ShanghaiTech University
Yong Ji: Nanjing Medical University
Qi Chen: Nanjing Medical University
Jingjing Ben: Nanjing Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Date: 2024
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DOI: 10.1038/s41467-024-48708-0

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