OTUD4 alleviates hepatic ischemia-reperfusion injury by suppressing the K63-linked ubiquitination of TRAF6

Biochem Biophys Res Commun. 2020 Mar 19;523(4):924-930. doi: 10.1016/j.bbrc.2019.12.114. Epub 2020 Jan 19.

Abstract

Hepatic ischemia-reperfusion (IR) injury can cause serious liver damage, leading to liver dysfunction after liver surgery, which is associated with NF-κB-mediated inflammation. The K63-linked auto-polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB. Here, we found that OTU domain-containing protein 4 (OTUD4), a deubiquitinating enzyme (DUB), interacts with TRAF6 and decreases the K63 auto-polyubiquitination of TRAF6. In addition, the data showed that NF-κB activation was impaired and inflammatory factor levels were reduced after overexpressing OTUD4 in a hypoxia/reoxygenation (HR) model and a hepatic IR model. Additionally, the liver inflammatory response and tissue damage were ameliorated in mice overexpressing OTUD4.Taken together, these results show that OTUD4 can negatively regulate NF-κB activation by suppressing the K63-linked ubiquitination of TRAF6, thus alleviating hepatic ischemia-reperfusion injury.

Keywords: Hepatic ischemia-reperfusion injury; K63 polyubiquitination; OTUD4; TRAF6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Inflammation Mediators / metabolism
  • Liver / metabolism*
  • Liver / pathology
  • Liver / physiopathology
  • Lysine / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • RAW 264.7 Cells
  • Reperfusion Injury / metabolism*
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination*

Substances

  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Otud4 protein, mouse
  • Ubiquitin-Specific Proteases
  • Lysine