The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

Meiners, Silke; Evankovich, John; Mallampalli, Rama K.

doi:10.1016/j.trsl.2018.03.003

Cited by 10 publications

(5 citation statements)

References 124 publications

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“…This is not surprising as MCHR1 modulates energy metabolism ( 11 ), likely in association with leptin ( 68 ). The biological process related to ubiquitination may affect SSc pathogenesis by modulating TGFβ signaling and TLR-dependent signaling ( 69 , 70 ). We also observed that the biological processes related to ECM remodeling and PDGF-BB signaling were perturbed when MCHR1 expression is silenced in NHDF, indicating that silencing of MCHR1 mediated the effects of PDGF-BB in the regulation of these genes, namely PDGFRA, PDGFRB, PDGFD, and MAPK9.…”

Section: Discussionmentioning

confidence: 99%

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

et al. 2021

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Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and excessive fibrosis of the skin and internal organs. To this day, no effective treatments to prevent the progression of fibrosis exist, and SSc patients have disabilities and reduced life expectancy. The need to better understand pathways that drive SSc and to find therapeutic targets is urgent. RNA sequencing data from SSc dermal fibroblasts suggested that melanin-concentrating hormone receptor 1 (MCHR1), one of the G protein-coupled receptors regulating emotion and energy metabolism, is abnormally deregulated in SSc. Platelet-derived growth factor (PDGF)-BB stimulation upregulated MCHR1 mRNA and protein levels in normal human dermal fibroblasts (NHDF), and MCHR1 silencing prevented the PDGF-BB-induced expression of the profibrotic factors transforming growth factor beta 1 (TGFβ1) and connective tissue growth factor (CTGF). PDGF-BB bound MCHR1 in membrane fractions of NHDF, and the binding was confirmed using surface plasmon resonance (SPR). MCHR1 inhibition blocked PDGF-BB modulation of intracellular cyclic adenosine monophosphate (cAMP). MCHR1 silencing in NHDF reduced PDGF-BB signaling. In summary, MCHR1 promoted the fibrotic response in NHDF through modulation of TGFβ1 and CTGF production, intracellular cAMP levels, and PDGF-BB-induced signaling pathways, suggesting that MCHR1 plays an important role in mediating the response to PDGF-BB and in the pathogenesis of SSc. Inhibition of MCHR1 should be considered as a novel therapeutic strategy in SSc-associated fibrosis.

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Section: Discussionmentioning

confidence: 99%

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

et al. 2021

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“…Concomitant with an increase in new protein synthesis is the need to degrade unwanted proteins via the ubiquitin-proteasome system. Indeed, increased activity of this proteolytic complex has been reported in fibrotic lung (4–6) and other organs (7), and in Fibs treated with pro-fibrotic mediators (6, 8, 9). At the molecular level, increased expression of ubiquitin ligases as well as proteasome subunits and their activators has been reported in fibrotic tissue and Fibs, including those from IPF patients (10–12).…”

Section: Introductionmentioning

confidence: 99%

Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

Penke

Speth²,

Wettlaufer³

et al. 2021

Preprint

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The FDA-approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential anti-fibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. Herein, we identify that therapeutic administration of BTZ in a mouse model of pulmonary fibrosis diminished the severity of fibrosis without reducing proteasome activity in the lung. Under conditions designed to mimic this lack of proteasome inhibition in vitro, it reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted de-differentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing expression of dual-specificity phosphatase 1 or DUSP1, and knockdown of DUSP1 abolished its anti-fibrotic actions in fibroblasts. Our findings identify a novel proteasome-independent mechanism of anti-fibrotic actions for BTZ and support its therapeutic repurposing for pulmonary fibrosis.

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“…The ubiquitin-proteasome system (UPS) is responsible for degradation of misregulated and damaged proteins to maintain protein homeostasis, and plays an essential role in cell proliferation, aging, apoptosis, and other major cellular processes. 1 A major regulatory step in the UPS is ubiquitination, a posttranslational modification that consists of the addition of the highly conserved 76 amino acid ubiquitin to a target protein via an adenosine triphosphate (ATP)-dependent process. First, the ubiquitin-activating enzyme (E1) forms a transient high-energy thiol with ubiquitin's C-terminal glycine residue in an ATP-dependent manner, followed by the transfer of ubiquitin to the active-site cysteine residue on the ubiquitin conjugation enzyme (E2).…”

Section: Introductionmentioning

confidence: 99%

“…The ubiquitin‐proteasome system (UPS) is responsible for degradation of misregulated and damaged proteins to maintain protein homeostasis, and plays an essential role in cell proliferation, aging, apoptosis, and other major cellular processes . A major regulatory step in the UPS is ubiquitination, a posttranslational modification that consists of the addition of the highly conserved 76 amino acid ubiquitin to a target protein via an adenosine triphosphate (ATP)‐dependent process.…”

Section: Introductionmentioning

confidence: 99%

Proteasome‐associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds

Castro

Ekinci

Huang

et al. 2019

J of Cellular Biochemistry

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The levels of organic pollutants, such as optical brightener (OB) compounds, in the global environment have been increasing in recent years. The toxicological effects and signal transduction systems associated with OB toxicity have not been thoroughly studied. The ubiquitin-proteasome system (UPS) plays a crucial role in regulating multiple essential cellular processes, and proteasomeassociated cysteine deubiquitinases (DUBs), ubiquitin C-terminal hydrolase L5 (UCHL5) and USP14, are two major regulators for (de)ubiquitination and stability of many important target proteins. Therefore, potential inhibition of UCHL5 and USP14 activities by some environmental chemicals might cause in vivo toxicity. In the current study we hypothesize that electrophilic OB compounds, such as 4,4′-diamino-2,2′-stilbenedisulfonic acid (DAST), fluorescent brightener 28 (FB-28) and FB-71, can interact with the catalytic triads (CYS, HIS, and ASP) of UCHL5 and USP14 and inhibit their enzymatic activities, leading to cell growth suppression. This hypothesis is supported by our findings presented in this study. Results from in silico computational docking and ubiquitin vinyl sulfone assay confirmed the UCHL5/USP14inhibitory activities of these OB compounds that have potencies in an order of: FB-71 > FB-28 > DAST. Furthermore, inhibition of these two proteasomal DUBs by OBs resulted in cell growth inhibition and apoptosis induction in two human breast cancer cell models. In addition, we found that OB-mediated DUB inhibition triggers a feedback reaction in which expression of UCHL5 and USP14 proteins is increased to compromise the suppressed activities. Our study suggests that these commonly used OB compounds may target and inhibit proteasomal cysteine DUBs, which should contribute to their toxicological effects in vivo. K E Y W O R D S degradation, environmental pollutant, fluorescent brightening agent, molecular target, posttranslational modification

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The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

Cited by 10 publications

References 124 publications

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

Proteasome‐associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds

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