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

摘要

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.