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.

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…4C). Analogous experiments using 4μ8c in the same animal model [using previously published doses that showed no toxicity (33,37,40,48)] produced similar results (Fig. 4 D-F): 4μ8c treatment led to a significant reduction (45.2%; P < 0.001) in atherosclerotic lesion area in en face aorta preparations (Fig.…”

Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver

“…Nrf2 activity is modulated by multiple mechanisms, including transcriptional regulation of Nrf2 gene, miRNA species-mediated control of Nrf2 mRNA, Keap1-mediated Nrf2 proteasome degradation, competition for binding to Keap1, ubiquitin ligase Hrd1-mediated Nrf2 ubiquitylation, kinase-induced posttranslational modification of Nrf2, and competition for binding to ARE. 17,42 These mechanisms may operate dynamically to regulate Nrf2 activity during liver regeneration. When Keap1 was knocked down, Nrf2 exhibited quiescence initially but activation later during the first wave of hepatocyte replication after PH.…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…88 Hrd1, an E3 ubiquitin ligase of the endoplasmic reticulum stress pathway, has been reported to target the Neh4 and Neh5 domain of Nrf2 for ubiquitination and degradation of Nrf2. 89 Up-regulation of Hrd1 suppresses Nrf2 expression and Nrf2-mediated antioxidant defense in human cirrhotic liver. 89 Phosphorylation of serine residues (Ser-334 and Ser-338 of DSGIS motif) in the Neh6 domain of Nrf2 by glycogen synthetase kinase 3b also promotes degradation of Nrf2 by b-TrCP, an adaptor protein of Cull3 ligase system.…”

“…89 Up-regulation of Hrd1 suppresses Nrf2 expression and Nrf2-mediated antioxidant defense in human cirrhotic liver. 89 Phosphorylation of serine residues (Ser-334 and Ser-338 of DSGIS motif) in the Neh6 domain of Nrf2 by glycogen synthetase kinase 3b also promotes degradation of Nrf2 by b-TrCP, an adaptor protein of Cull3 ligase system. 90 The role of these E3 ubiquitin ligases in context of aging and fibrosis is not well understood, although a general decline in the function of the ubiquitin-proteosomal system with aging is well appreciated.…”