ARRB1 ameliorates liver ischaemia/reperfusion injury via antagonizing TRAF6-mediated Lysine 6-linked polyubiquitination of ASK1 in hepatocytes.
J Cell Mol Med
; 24(14): 7814-7828, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32445435
ABSTRACT
Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in-depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. ß-arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver-specific diseases. However, the role and underlying mechanism of ß-arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down-regulated during liver I/R injury. Hepatocyte-specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro-inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6-mediated Lysine 6-linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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MAP Quinase Quinase Quinase 5
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Fator 6 Associado a Receptor de TNF
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Beta-Arrestina 1
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Hepatopatias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article