Hypothermic oxygenated perfusion inhibits HECTD3-mediated TRAF3 polyubiquitination to alleviate DCD liver ischemia-reperfusion injury

Autor: Qiuyan Zhang, Zibiao Zhong, Yanfeng Wang, Wei Zhou, Anxiong Liu, Sheng Peng, Zhongshan Lu, Qifa Ye, Danni Lin, Haoyang Xia, Shaojun Ye, Zhongzhong Liu
Rok vydání: 2020
Předmět:
0301 basic medicine
HECT domain
Male
Cancer Research
Molecular biology
medicine.medical_treatment
Diseases
Liver transplantation
Pharmacology
Rats
Sprague-Dawley
0302 clinical medicine
Hypothermia
Induced
biology
lcsh:Cytology
Organ Preservation
Cell Hypoxia
Ubiquitin ligase
Perfusion
medicine.anatomical_structure
Liver
030220 oncology & carcinogenesis
Hepatocyte
Reperfusion Injury
Tissue and Organ Harvesting
medicine.symptom
Inflammation Mediators
Liver Circulation
Ubiquitin-Protein Ligases
Immunology
Cold storage
Inflammation
Article
Cell Line
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
Hepatectomy
Humans
lcsh:QH573-671
TNF Receptor-Associated Factor 3
business.industry
Ubiquitination
Correction
Cell Biology
Hypoxia (medical)
medicine.disease
Liver Transplantation
Disease Models
Animal
Oxidative Stress
030104 developmental biology
biology.protein
business
Reperfusion injury
Zdroj: Cell Death & Disease
Cell Death and Disease, Vol 12, Iss 2, Pp 1-17 (2021)
ISSN: 2041-4889
Popis: Ischemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.
Databáze: OpenAIRE
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