|
KMID : 0620920230550061218
|
|
Experimental & Molecular Medicine
2023 Volume.55 No. 6 p.1218 ~ p.1231
|
|
|
Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3β phosphorylation and mitochondrial translocation
|
|
Lee Jae-won
Ha Ji-Hoon
Kim Jun-Hyeong
Seo Dong-Yeob
Kim Min-Beom
Lee Ye-Rin
Park Seong-Shil
Choi Da-Hee
Park Jin-Seok
Lee Young-Jae
Yang Kyung-Min
Jung Su-Myung
Hong Sun-Taek
Koo Seung-Hoi
Bae Yong-Soo
Kim Seong-Jin
Park Seok-Hee
|
|
|
Abstract
|
|
|
|
The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3?/? knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3β were decreased in primary hepatocytes obtained from Peli3?/? KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3β compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3β. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3?/? KO hepatocytes restored the mitochondrial translocation of GSK3β, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3β polyubiquitination.
|
|
|
KEYWORD
|
|
|
Experimental models of disease, Ubiquitylation
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
|
|