Ubiquitin-specific protease 29 attenuates hepatic ischemia-reperfusion injury by mediating TGF-β-activated kinase 1 deubiquitination

Zhongbao Chen; Fengjiao Hu; Yalong Zhang; Long Zhang; Tianyu Wang; Chenyang Kong; Haochong Hu; Jiayu Guo; Qi Chen; Bo Yu; Yiting Liu; Jilin Zou; Jiangqiao Zhou; Tao Qiu

doi:10.3389/fimmu.2023.1167667

Ubiquitin-specific protease 29 attenuates hepatic ischemia-reperfusion injury by mediating TGF-β-activated kinase 1 deubiquitination

Front Immunol. 2023 May 26:14:1167667. doi: 10.3389/fimmu.2023.1167667. eCollection 2023.

Authors

Zhongbao Chen^{1

2}, Fengjiao Hu³, Yalong Zhang^{1

2}, Long Zhang^{1

2}, Tianyu Wang^{1

2}, Chenyang Kong^{1

2}, Haochong Hu^{1

2}, Jiayu Guo^{1

2}, Qi Chen^{1

2}, Bo Yu^{1

2}, Yiting Liu^{1

2}, Jilin Zou^{1

2}, Jiangqiao Zhou^{1

2}, Tao Qiu^{1

2}

Affiliations

¹ Department of Organ Transplantation, Renmin Hospital, Wuhan University, Wuhan, China.
² Department of Urology, Renmin Hospital, Wuhan University, Wuhan, China.
³ Medical Science Research Centre, Zhongnan Hospital, Wuhan University, Wuhan, China.

Abstract

Background and aims: In the course of clinical practice, hepatic ischemia/reperfusion (I/R) injury is a prevalent pathophysiological event and is caused by a combination of complex factors that involve multiple signaling pathways such as MAPK and NF-κB. USP29 is a deubiquitinating enzyme important during the development of tumors, neurological diseases, and viral immunity. However, it is unknown how USP29 contributes to hepatic I/R injury.

Methods and results: We systematically investigated the role of the USP29/TAK1-JNK/p38 signaling pathway in hepatic I/R injury. We first found reduced USP29 expression in both mouse hepatic I/R injury and the primary hepatocyte hypoxia-reoxygenation (H/R) models. We established USP29 full knockout mice (USP29-KO) and hepatocyte-specific USP29 transgenic mice (USP29-HTG), and we found that USP29 knockout significantly exacerbates the inflammatory infiltration and injury processes during hepatic I/R injury, whereas USP29 overexpression alleviates liver injury by decreasing the inflammatory response and inhibiting apoptosis. Mechanistically, RNA sequencing results showed the effects of USP29 on the MAPK pathway, and further studies revealed that USP29 interacts with TAK1 and inhibits its k63-linked polyubiquitination, thereby preventing the activation of TAK1 and its downstream signaling pathways. Consistently, 5z-7-Oxozeaneol, an inhibitor of TAK1, blocked the detrimental effects of USP29 knockout on H/R-induced hepatocyte injury, further confirming that USP29 plays a regulatory role in hepatic I/R injury by targeting TAK1.

Conclusion: Our findings imply that USP29 is a therapeutic target with promise for the management of hepatic I/R injury via TAK1-JNK/p38 pathway-dependent processes.

Keywords: TAK1; Usp29; apoptosis; deubiquitination; hepatic ischemia-reperfusion injury; inflammation; phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Liver
MAP Kinase Kinase Kinases* / genetics
Mice
Mice, Knockout
Mice, Transgenic
Reperfusion Injury* / genetics
Ubiquitin-Specific Proteases / genetics

Substances

MAP kinase kinase kinase 7
MAP Kinase Kinase Kinases
Ubiquitin-Specific Proteases
Usp29 protein, mouse

Grants and funding

This work was supported by the National Natural Science Foundation of China (NSFC) Grants (81870067,82170664,82000600), The Science and Technology Planning Project of Wuhan(2020020601012213).