Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia-Reperfusion Injury in Mice.

Abstract

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.

• Authors: Zhen-Zhen Yan, Yong-Ping Huang, Xin Wang, Hai-Ping Wang, Fei Ren, Rui-Feng Tian, Xu Cheng, Jie Cai, Yan Zhang, Xue-Yong Zhu, Zhi-Gang She, Xiao-Jing Zhang, Zan Huang, Hongliang Li
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 70 Issue 5 Pg. 1750-1769 (11 2019) ISSN: 1527-3350 [Electronic] United States
• PMID: 31077413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by the American Association for the Study of Liver Diseases.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Tollip protein, mouse

Topics

• Animals
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, physiology)
• Liver (blood supply)
• Male
• Mice
• Mice, Inbred C57BL
• Proteomics
• Reperfusion Injury (drug therapy, etiology)