期刊
HEPATOLOGY
卷 70, 期 5, 页码 1750-1769出版社
WILEY
DOI: 10.1002/hep.30705
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资金
- Fundamental Research Funds for the Central Universities [2042017kf0198] Funding Source: Medline
- General Program of National Natural Science Foundation of China [81870427] Funding Source: Medline
- Major Research Plan of the National Natural Science Foundation of China [91639304, 91729303] Funding Source: Medline
- National Science Fund for Distinguished Young Scholars [81425005] Funding Source: Medline
- Creative Groups Project of Hubei Province [2016CFA010] Funding Source: Medline
- Guiding Fund of Renmin Hospital of Wuhan University [RMYD2018M01] Funding Source: Medline
- National Key Research and Development Program of China [2016YFF0101504] Funding Source: Medline
- Key Project of the National Natural Science Foundation [81630011] Funding Source: Medline
- Hubei Science and Technology Support Project [2018BEC473] Funding Source: Medline
Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.
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