Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

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

Research output: Contribution to journalArticle

97 Citations (Scopus)

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

Fingerprint

Endoplasmic Reticulum Stress
Liver Cirrhosis
Reactive Oxygen Species
Down-Regulation
End Stage Liver Disease
Ubiquitin-Protein Ligases
Ubiquitination
Liver
Ligases
Ubiquitin
Knockout Mice
Oxidative Stress
Up-Regulation
Antioxidants
Therapeutics

Keywords

  • Hrd1
  • Liver cirrhosis
  • Nrf2

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. / Wu, Tongde; Zhao, Fei; Gao, Beixue; Tan, Can; Yagishita, Naoko; Nakajima, Toshihiro; Wong, Pak Kin; Chapman, Eli; Fang, Deyu; Zhang, Donna.

In: Genes and Development, Vol. 28, No. 7, 01.04.2014, p. 708-722.

Research output: Contribution to journalArticle

Wu T, Zhao F, Gao B, Tan C, Yagishita N, Nakajima T et al. Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes and Development. 2014 Apr 1;28(7):708-722. https://doi.org/10.1101/gad.238246.114
Wu, Tongde ; Zhao, Fei ; Gao, Beixue ; Tan, Can ; Yagishita, Naoko ; Nakajima, Toshihiro ; Wong, Pak Kin ; Chapman, Eli ; Fang, Deyu ; Zhang, Donna. / Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. In: Genes and Development. 2014 ; Vol. 28, No. 7. pp. 708-722.
@article{9c3c8b8cde734f8cbfb3f233fe9de8b1,
title = "Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis",
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.",
keywords = "Hrd1, Liver cirrhosis, Nrf2",
author = "Tongde Wu and Fei Zhao and Beixue Gao and Can Tan and Naoko Yagishita and Toshihiro Nakajima and Wong, {Pak Kin} and Eli Chapman and Deyu Fang and Donna Zhang",
year = "2014",
month = "4",
day = "1",
doi = "10.1101/gad.238246.114",
language = "English (US)",
volume = "28",
pages = "708--722",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "7",

}

TY - JOUR

T1 - Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

AU - Wu, Tongde

AU - Zhao, Fei

AU - Gao, Beixue

AU - Tan, Can

AU - Yagishita, Naoko

AU - Nakajima, Toshihiro

AU - Wong, Pak Kin

AU - Chapman, Eli

AU - Fang, Deyu

AU - Zhang, Donna

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

AB - 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.

KW - Hrd1

KW - Liver cirrhosis

KW - Nrf2

UR - http://www.scopus.com/inward/record.url?scp=84898874270&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898874270&partnerID=8YFLogxK

U2 - 10.1101/gad.238246.114

DO - 10.1101/gad.238246.114

M3 - Article

VL - 28

SP - 708

EP - 722

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 7

ER -