The E3 ubiquitin ligase NEDD4-1 protects against acetaminophen-induced liver injury by targeting VDAC1 for degradation.

Yiwei Zhu; Lin Lei; Xinghui Wang; Linfang Chen; Wei LI; Jinxia LI; Chenchen Zhao; Xiliang DU; Yuxiang Song; Wenwen Gao; Guowen Liu; Xinwei LI

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The E3 ubiquitin ligase NEDD4-1 protects against acetaminophen-induced liver injury by targeting VDAC1 for degradation.

Author: Yiwei ZHU ¹ ; Lin LEI ¹ ; Xinghui WANG ¹ ; Linfang CHEN ¹ ; Wei LI ¹ ; Jinxia LI ¹ ; Chenchen ZHAO ¹ ; Xiliang DU ¹ ; Yuxiang SONG ¹ ; Wenwen GAO ¹ ; Guowen LIU ¹ ; Xinwei LI ¹
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1. State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
Publication Type:Journal Article
Keywords: Acetaminophen; Hepatotoxicity; Liver injury; Mitochondrial damage; NEDD4-1; Necrosis; Ubiquitination; VDAC1
From: Acta Pharmaceutica Sinica B 2023;13(4):1616-1630
CountryChina
Language:English
Abstract: Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.