Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells

Abstract

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of transforming growth factor-β (TGFβ), connective tissue growth factor (CTGF), interferon-γ (IFNγ) and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN), fibronectin EDA domain (FN EDA), metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-1 (TIMP-1) and peroxisome proliferator-associated receptor-γ (PPARγ) was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFβ gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARγ. In addition, both CTGF and TGFβ were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses.

Trauma and posttraumatic stress interact with sex-specific risk loci for suicidality and converge on brain extracellular matrix biology and synaptic plasticity

“…51,52 The ubiquitin-proteasome system, of which the PSMD14 gene product is a component, plays a critical role in the expression of ECM-associated genes. 53 Most notable is CNTN5, previously detected by a SNPbased GWAS of suicidality also performed in the UKB -a finding that is consistent, but that made use of some of the same information included herein. Its product, contactin-5 is part of the glycosylphosphatidylinositol-bound protein family that has often been implicated in autism spectrum disorder.…”

Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells

“…Interestingly, the proteasome activity was upregulated by a low concentration of CURC and inhibited by a high concentration of CURC [62]. These different dose-dependent effects on proteasome activity might be, at least in part, explained by the evidence demonstrating that CURC could act as both a pro-oxidative and anti-oxidative molecule [64]. Moreover, differences in experimental conditions, such as CURC concentrations, duration of the treatments and especially cell types, may contribute to explain the variability observed on the effects of this polyphenol on the proteasome activity/expression.…”

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

“…Though previously associated with psychiatric disorders, detection of HEPN1 is likely attributed to colocalization of HEPN1 and HEPACAM ( Chung Moh et al, 2005 ). The ubiquitin-proteasome system, of which the PSMD14 gene product is a component, plays a critical role in the expression of ECM-associated genes ( Ramos de Carvalho et al, 2018 ). CNTN5 was previously detected by GWAS of suicidality also performed in the UKB – a finding that is consistent, but not wholly independent from the information included herein.…”