한빛사논문
- 조회416
Jaewon Lee1,9, Jihoon Ha1,9, Jun-Hyeong Kim1,8,9, Dongyeob Seo1, Minbeom Kim1, Yerin Lee1, Seong Shil Park1, Dahee Choi2, Jin Seok Park1, Young Jae Lee3, Siyoung Yang4,5, Kyung-Min Yang6, Su Myung Jung1, Suntaek Hong3, Seung-Hoi Koo2, Yong-Soo Bae1,5, Seong-Jin Kim6,7 and Seok Hee Park1,5
1Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
2Department of Life Science, Korea University, Seoul 02841, Republic of Korea.
3Department of Biochemistry, Gachon University School of Medicine, Incheon 21999, Republic of Korea.
4Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Republic of Korea.
5SRC Center for Immune Research on Non-lymphoid Organs, Sungkyunkwan University, Suwon 16419, Republic of Korea.
6Medpacto Inc., Seoul 06668, Republic of Korea.
7GILO Institute, GILO Foundation, Seoul 06668, Republic of Korea.
8Present address: KoBio Labs, Seongnam 13488, Republic of Korea.
9These authors contributed equally: Jaewon Lee, Jihoon Ha, Jun-Hyeong Kim.
Corresponding authors : Correspondence to Seong-Jin Kim or Seok Hee Park.
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.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-06-15)
- 국내 연구진
- 생명과학 > 세포생물학
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