Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

Wilson, Caroline; Murphy, Lindsay B.; Leslie, Jack; Kendrick, Stuart; French, Jeremy; Fox, Colin; Sheerin, Neil; Fisher, Andrew J.; Robinson, John H.; Tiniakos, Dina; Gray, Douglas A.; Oakley, Fiona; Mann, Derek A.

doi:10.1016/j.jhep.2015.07.034

Cited by 48 publications

(59 citation statements)

References 36 publications

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“…Ubiquitin C-terminal hydrolase 1 (UCHL1), a deubiquitinase, is up-regulated following HSC activation, and promote their proliferation in CCl 4 and BDL mice [306]. Small molecule UCHL1 inhibitor, LDN-57444, attenuates PDGF-induced HSC proliferation by modulating phosphorylation of a cell cycle regulator, retinoblastoma protein (Rb).…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,042

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,042

894

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“…Ubiquitin C-terminal hydrolase 1 (UCHL1, also known as PARK5/ PGP9.5), is a DUB responsible for removing ubiquitin or polyubiquitin from target proteins (7,8). It is highly dysregulated and plays critical roles in several disorders, including tumors, neurodegenerative diseases, and liver fibrosis (8,9). One study reported that UCHL1 influences skeletal muscle development and function.…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

Zhang

et al. 2020

Sci. Adv.

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Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1-treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy. The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor. Sci. Adv. 6, eaax4826 (2020).

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“…According to Wilson et al, UCHL1 'can also interact and stabilize cell proteins such as b catenin, and activate kinases such as CDK4 without the requirement for its enzymatic activity' that has both hydrolase and ligase activities [48]. According to Zhang et al [49]: 'UCHL1 is expressed predominantly in the brain and neuroendocrine systems, and accounts for 1-2% of total brain soluble proteins'.…”

Section: Discussionmentioning

confidence: 99%

“…Concentrations of UCHL1 in the blood plasma of children with appendicitis g1, before surgery, g2, 24 h after surgery and g3, 72 h after appendectomy; ctrl 5 control group. et al [48] shows that: 'pharmacological inhibition of UCHL1 blocks hepatic stellate cells proliferation and when administered in vivo acts in a therapeutic way to block progression of established fibrosis despite continued liver injury'. Despite many functions identified so far, there are no data available in the literature on the correlation of expression of UCHL1 and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors

Matuszczak

Sankiewicz

Dębek

et al. 2017

Clinical and Experimental Immunology

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SummaryThe aim of this study was to determinate the immunoproteasome concentration in the blood plasma of children with appendicitis, and its correlation with circulating proteasome and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Twenty-seven children with acute appendicitis, managed at the Paediatric Surgery Department, were included randomly into the study (age 2 years 9 months up to 14 years, mean age 9Á5 6 1 years). There were 10 girls and 17 boys; 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Mean concentrations of immunoproteasome, 20S proteasome and UCHL1 in the blood plasma of children with appendicitis before surgery 24 h and 72 h after the appendectomy were higher than in the control group. The immunoproteasome, 20S proteasome and UCHL1 concentrations in the blood plasma of patients with acute appendicitis were highest before surgery. The immunoproteasome, 20S proteasome and UCHL1 concentration measured 24 and 72 h after the operation decreased slowly over time and still did not reach the normal range (P < 0Á05). There was no statistical difference between immunoproteasome, 20S proteasome and UCHL1 concentrations in children operated on laparoscopically and children after classic appendectomy. The immunoproteasome concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation may thus be helpful in the assessment of the efficacy of treatment. The method of operation -classic open appendectomy or laparoscopic appendectomy -does not influence the general trend in immunoproteasome concentration in children with appendicitis.

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Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

Cited by 48 publications

References 36 publications

Hepatic stellate cells as key target in liver fibrosis

Hepatic stellate cells as key target in liver fibrosis

The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors

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