Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

Tongde Wu, Fei Zhao, Beixue Gao, Can Tan, Naoko Yagishita, Toshihiro Nakajima, Pak K. Wong, Eli Chapman, Deyu Fang, Donna D. Zhang

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Downregulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

Original languageEnglish (US)
Pages (from-to)708-722
Number of pages15
JournalGenes and Development
Volume28
Issue number7
DOIs
StatePublished - Apr 1 2014

Keywords

  • Hrd1
  • Liver cirrhosis
  • Nrf2

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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