Abstract:Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned
synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic
reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in
rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of
synoviolin activity is a potentially useful therapeutic approach for the treatment of RA.
We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin
autoubi… Show more
“…LS-102 suppressed down-regulation of Nrf2 and its target genes induced by CCl 4 treatment while having no effect on the protein levels of XBP1s and Hrd1, consistent with its mode of action ( Fig. 7A,B; Yagishita et al 2012). Although the expression pattern of XBP1s and Hrd1 in response to both inhibitors was similar in Nrf2 +/+ and Nrf2 À/À mice, the expression levels of NQO1 and GCLM remained the same in the inhibitor-treated Nrf2 À/À groups (Fig.…”
Section: Hrd1 Is a Novel E3 Ubiquitin Ligase Of Nrf2supporting
confidence: 70%
“…Therefore, we tested whether Hrd1 is a potential therapeutic target for preventing/ mitigating liver cirrhosis through enhancement of the Nrf2-regulated protective mechanism. Two compounds, 4U8C (IRE1 inhibitor) (Cross et al 2012;Qiu et al 2013) and LS-102 (Hrd1 inhibitor) (Yagishita et al 2012), were tested for their ability to alleviate liver cirrhosis in Nrf2 +/+ and Nrf2 À/À mice. In Nrf2 +/+ mice, CCl 4 increased XBP1s and Hrd1 protein levels while decreasing Nrf2, NQO1, and GCLM protein levels (Fig.…”
Section: Hrd1 Is a Novel E3 Ubiquitin Ligase Of Nrf2mentioning
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.
“…LS-102 suppressed down-regulation of Nrf2 and its target genes induced by CCl 4 treatment while having no effect on the protein levels of XBP1s and Hrd1, consistent with its mode of action ( Fig. 7A,B; Yagishita et al 2012). Although the expression pattern of XBP1s and Hrd1 in response to both inhibitors was similar in Nrf2 +/+ and Nrf2 À/À mice, the expression levels of NQO1 and GCLM remained the same in the inhibitor-treated Nrf2 À/À groups (Fig.…”
Section: Hrd1 Is a Novel E3 Ubiquitin Ligase Of Nrf2supporting
confidence: 70%
“…Therefore, we tested whether Hrd1 is a potential therapeutic target for preventing/ mitigating liver cirrhosis through enhancement of the Nrf2-regulated protective mechanism. Two compounds, 4U8C (IRE1 inhibitor) (Cross et al 2012;Qiu et al 2013) and LS-102 (Hrd1 inhibitor) (Yagishita et al 2012), were tested for their ability to alleviate liver cirrhosis in Nrf2 +/+ and Nrf2 À/À mice. In Nrf2 +/+ mice, CCl 4 increased XBP1s and Hrd1 protein levels while decreasing Nrf2, NQO1, and GCLM protein levels (Fig.…”
Section: Hrd1 Is a Novel E3 Ubiquitin Ligase Of Nrf2mentioning
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.
“…Figure 7.Rescue of V247M mutant in V247M cells after pharmacological inhibition of the E3 ligase HRD1. ( A ) V247M cells were treated for 8 h with either 15 μ m LS-101 or 20 μ m LS-102, specific HRD1 ligase inhibitors (37). DMSO, the vehicle of HRD1 inhibitors, was used as negative control.…”
Many membrane and secretory proteins that fail to pass quality control in the endoplasmic reticulum (ER) are dislocated into the cytosol and degraded by the proteasome. In applying rigid rules, however, quality control sometimes discharges proteins that, even though defective, retain their function. The unnecessary removal of such proteins represents the pathogenetic hallmark of diverse genetic diseases, in the case of ΔF508 mutant of cystic fibrosis transmembrane conductance regulator being probably the best known example. Recently, the inappropriate proteasomal degradation of skeletal muscle sarcoglycans (α, β, γ and δ) with missense mutation has been proposed to be at the bases of mild-to-severe forms of limb girdle muscular dystrophy (LGMD) known as type 2D, 2E, 2C and 2F, respectively. The quality control pathway responsible for sarcoglycan mutant disposal, however, is so far unexplored. Here we reveal key components of the degradative route of V247M α-sarcoglycan mutant, the second most frequently reported mutation in LGMD-2D. The disclosure of the pathway, which is led by the E3 ligases HRD1 and RFP2, permits to identify new potential druggable targets of a disease for which no effective therapy is at present available. Notably, we show that the pharmacological inhibition of HRD1 activity rescues the expression of V247-α-sarcoglycan both in a heterologous cell model and in myotubes derived from a LGMD-2D patient carrying the L31P/V247M mutations. This represents the first evidence that the activity of E3 ligases, the enzymes in charge of mutant fate, can be eligible for drug interventions to treat sarcoglycanopathy.
“…Using HTS, two classes of small molecules have been identifi ed that effi ciently inhibit synoviolin activity by inhibition of autoubiquitination enzymatic activity, thus blocking proliferation of synovial cells. This inhibitor has been in preclinical development since 2011 (Yagishita et al 2012 ).…”
Section: Inhibitors Of Other E3 Ubiquitin Ligasesmentioning
The Ubiquitin-Proteasome System (UPS) plays an important role in the setting of the cellular response to multiple stress signals. Although the primary function of ubiquitin was initially associated with proteolysis, it is now considered as a key regulator of protein function controlling, among other functions, signalling cascades, transcription, apoptosis or oncogenesis. Failure at any level of the UPS is associated with the development of multiple pathologies including metabolic problems, immune diseases, infl ammation and cancer. The successful use of the proteasome inhibitor Bortezomib (Velcade) in the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) revealed the potential of the UPS as pharmacological target. Ten years later, new inhibitors tackling not only the proteasome but also different subsets of enzymes which conjugate or de-conjugate ubiquitin or ubiquitin-like molecules, have been developed. Most of them are excellent tools to characterize better the emerging molecular mechanisms regulating distinct critical cellular processes. Some of them have been launched already while many others are still in pre-clinical development. This chapter updates some of the most successful efforts to develop and characterize inhibitors of the UPS which tackle mechanisms involved in cancer. Particular attention has been dedicated to updating the status of the clinical trials of these inhibitors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
