PMID- 37258579
OWN - NLM
STAT- MEDLINE
DCOM- 20230705
LR  - 20240115
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 55
IP  - 6
DP  - 2023 Jun
TI  - Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition 
      of GSK3beta phosphorylation and mitochondrial translocation.
PG  - 1218-1231
LID - 10.1038/s12276-023-01009-w [doi]
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Lee, Jaewon
AU  - Lee J
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Ha, Jihoon
AU  - Ha J
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Kim, Jun-Hyeong
AU  - Kim JH
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
AD  - KoBio Labs, Seongnam, 13488, Republic of Korea.
FAU - Seo, Dongyeob
AU  - Seo D
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Kim, Minbeom
AU  - Kim M
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Lee, Yerin
AU  - Lee Y
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Park, Seong Shil
AU  - Park SS
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Choi, Dahee
AU  - Choi D
AD  - Department of Life Science, Korea University, Seoul, 02841, Republic of Korea.
FAU - Park, Jin Seok
AU  - Park JS
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Lee, Young Jae
AU  - Lee YJ
AUID- ORCID: 0000-0002-3841-1994
AD  - Department of Biochemistry, Gachon University School of Medicine, Incheon, 21999, 
      Republic of Korea.
FAU - Yang, Siyoung
AU  - Yang S
AD  - Department of Pharmacology, Ajou University School of Medicine, Suwon, 16499, 
      Republic of Korea.
AD  - SRC Center for Immune Research on Non-lymphoid Organs, Sungkyunkwan University, 
      Suwon, 16419, Republic of Korea.
FAU - Yang, Kyung-Min
AU  - Yang KM
AD  - Medpacto Inc., Seoul, 06668, Republic of Korea.
FAU - Jung, Su Myung
AU  - Jung SM
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
FAU - Hong, Suntaek
AU  - Hong S
AD  - Department of Biochemistry, Gachon University School of Medicine, Incheon, 21999, 
      Republic of Korea.
FAU - Koo, Seung-Hoi
AU  - Koo SH
AUID- ORCID: 0000-0001-8769-2879
AD  - Department of Life Science, Korea University, Seoul, 02841, Republic of Korea.
FAU - Bae, Yong-Soo
AU  - Bae YS
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea.
AD  - SRC Center for Immune Research on Non-lymphoid Organs, Sungkyunkwan University, 
      Suwon, 16419, Republic of Korea.
FAU - Kim, Seong-Jin
AU  - Kim SJ
AUID- ORCID: 0000-0003-4335-8793
AD  - Medpacto Inc., Seoul, 06668, Republic of Korea. jasonsjkim@gilo.or.kr.
AD  - GILO Institute, GILO Foundation, Seoul, 06668, Republic of Korea. 
      jasonsjkim@gilo.or.kr.
FAU - Park, Seok Hee
AU  - Park SH
AUID- ORCID: 0000-0002-6210-4927
AD  - Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, 
      Republic of Korea. parks@skku.edu.
AD  - SRC Center for Immune Research on Non-lymphoid Organs, Sungkyunkwan University, 
      Suwon, 16419, Republic of Korea. parks@skku.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230601
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - 362O9ITL9D (Acetaminophen)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Acetaminophen/adverse effects
MH  - Phosphorylation
MH  - Glycogen Synthase Kinase 3 beta/genetics/metabolism
MH  - *Chemical and Drug Induced Liver Injury, Chronic/metabolism
MH  - Liver/metabolism
MH  - Hepatocytes/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
MH  - Mice, Inbred C57BL
PMC - PMC10318043
COIS- The authors declare no competing interests.
EDAT- 2023/06/01 01:08
MHDA- 2023/07/05 06:42
PMCR- 2023/06/01
CRDT- 2023/05/31 23:19
PHST- 2022/08/15 00:00 [received]
PHST- 2023/03/15 00:00 [accepted]
PHST- 2023/02/07 00:00 [revised]
PHST- 2023/07/05 06:42 [medline]
PHST- 2023/06/01 01:08 [pubmed]
PHST- 2023/05/31 23:19 [entrez]
PHST- 2023/06/01 00:00 [pmc-release]
AID - 10.1038/s12276-023-01009-w [pii]
AID - 1009 [pii]
AID - 10.1038/s12276-023-01009-w [doi]
PST - ppublish
SO  - Exp Mol Med. 2023 Jun;55(6):1218-1231. doi: 10.1038/s12276-023-01009-w. Epub 2023 
      Jun 1.