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논문 기본 정보

자료유형
학술저널
저자정보
Lee Jaewon (Sungkyunkwan University) Ha Jihoon (Sungkyunkwan University) Kim Jun-Hyeong (Sungkyunkwan University) Seo Dongyeob (Sungkyunkwan University) Kim Minbeom (Sungkyunkwan University) Lee Yerin (Sungkyunkwan University) Park Seong Shil (Sungkyunkwan University) Choi Dahee (Korea University) Park Jin Seok (Sungkyunkwan University) Lee Young Jae (Gachon University School of Medicine) Yang Siyoung (Ajou University School of Medicine) Yang Kyung-Min (Medpacto Inc.) Jung Su Myung (Sungkyunkwan University) Hong Suntaek (Gachon University School of Medicine) Koo Seung-Hoi (Korea University) Bae Yong-Soo (Sungkyunkwan University) Kim Seong-Jin (Medpacto Inc.) Park Seok Hee (Sungkyunkwan University)
저널정보
대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제55권
발행연도
2023.6
수록면
1,218 - 1,231 (14page)
DOI
10.1038/s12276-023-01009-w

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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.

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