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

• DOI: 10.1016/j.apsb.2023.01.019
• Publication Date: 2023-01-29T14:57:55Z
• Authors: Yiwei Zhu; Lin Lei; Xinghui Wang; Linfang Chen; Wei Li; Jinxia Li; Chenchen Zhao; Xiliang Du; Yuxiang Song; Wenwen Gao; Guowen Liu; Xinwei Li
• Keywords: 0301 basic medicine; VDAC1; Necrosis; 03 medical and health sciences; Hepatotoxicity; Original Article; Therapeutics. Pharmacology; RM1-950; Liver injury; NEDD4-1; 3. Good health; Acetaminophen

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.