| First Author | Lee J | Year | 2023 |
| Journal | Exp Mol Med | Volume | 55 |
| Issue | 6 | Pages | 1218-1231 |
| PubMed ID | 37258579 | Mgi Jnum | J:353497 |
| Mgi Id | MGI:7505818 | Doi | 10.1038/s12276-023-01009-w |
| Citation | Lee J, et al. (2023) Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3beta phosphorylation and mitochondrial translocation. Exp Mol Med 55(6):1218-1231 |
| abstractText | 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 GSK3beta 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 GSK3beta compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3beta. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3(-/-) KO hepatocytes restored the mitochondrial translocation of GSK3beta, 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 GSK3beta polyubiquitination. |
