Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity

Huo, Huanhuan; Yang, Cuiwei; Zhang, Tao; Chu, Yuanyuan; Liu, Yanfen

doi:10.1016/j.bbrc.2018.02.140

Cited by 22 publications

(18 citation statements)

References 35 publications

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“…Pacelli and colleagues [34] have described SEMA7A as a modulator of ROS-mediated neurodegeneration, by demonstrating that SEMA7A can reduce DAn axonal arborization and vulnerability through its capability to the decrease mitochondrial oxygen demanding and ROS production. Concerning UHCL1, ubiquitin plays a crucial role in the maintenance of the ubiquitin-proteasome system (UPS), which has been suggested as being involved in the initiation and progression of PD [35,36]. In fact, in PD brain tissue, UCHL1 is present in Lewy bodies, displaying an import role in maintaining UPS pool and DAn cell survival [36].…”

Section: Discussionmentioning

confidence: 99%

“…Concerning UHCL1, ubiquitin plays a crucial role in the maintenance of the ubiquitin-proteasome system (UPS), which has been suggested as being involved in the initiation and progression of PD [35,36]. In fact, in PD brain tissue, UCHL1 is present in Lewy bodies, displaying an import role in maintaining UPS pool and DAn cell survival [36]. Nevertheless, although UCHL1 is involved in a genetic form of PD [37], its functions in (normal physiological conditions) living cells and tissues are still poorly understood, with several studies assuming UCHL-1 dysfunction associated to ubiquitinated proteins accumulation, as alpha-synuclein, the major cause of DAn cell degeneration [38,39].…”

Section: Discussionmentioning

confidence: 99%

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Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Teixeira

Vilaça-Faria

Domingues

et al. 2020

Cells

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Parkinson’s Disease (PD) is characterized by the massive loss of dopaminergic neurons, leading to the appearance of several motor impairments. Current pharmacological treatments, such as the use of levodopa, are yet unable to cure the disease. Therefore, there is a need for novel strategies, particularly those that can combine in an integrated manner neuroprotection and neuroregeneration properties. In vitro and in vivo models have recently revealed that the secretome of mesenchymal stem cells (MSCs) holds a promising potential for treating PD, given its effects on neural survival, proliferation, differentiation. In the present study, we aimed to access the impact of human bone marrow MSCs (hBM-MSCs) secretome in 6-hydroxydopamine (6-OHDA) PD model when compared to levodopa administration, by addressing animals’ motor performance, and substantia nigra (SN), and striatum (STR) histological parameters by tyrosine hydroxylase (TH) expression. Results revealed that hBM-MSCs secretome per se appears to be a modulator of the dopaminergic system, enhancing TH-positive cells expression (e.g., dopaminergic neurons) and terminals both in the SN and STR when compared to the untreated group 6-OHDA. Such finding was positively correlated with a significant amelioration of the motor outcomes of 6-OHDA PD animals (assessed by the staircase test). Thus, the present findings support hBM-MSCs secretome administration as a potential therapeutic tool in treating PD, and although we suggest candidate molecules (Trx1, SEMA7A, UCHL1, PEDF, BDNF, Clusterin, SDF-1, CypA, CypB, Cys C, VEGF, DJ-1, Gal-1, GDNF, CDH2, IL-6, HSP27, PRDX1, UBE3A, MMP-2, and GDN) and possible mechanisms of hBM-MSCs secretome-mediated effects, further detailed studies are needed to carefully and clearly define which players may be responsible for its therapeutic actions. By doing so, it will be reasonable to presume that potential treatments that can, per se, or in combination modulate or slow PD may lead to a rational design of new therapeutic or adjuvant strategies for its functional modeling and repair.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Teixeira

Vilaça-Faria

Domingues

et al. 2020

Cells

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“…LDN is a potent reversible, competitive and active site-directed inhibitor of UCHL1. The administration of LDN aggravates mossy fiber sprouting and induces LC3 puncta formation and autophagy in the HeLa cell line and apoptosis through the activation of endoplasmic reticulum stress (ERS) [33,34]. Here, our results demonstrated that the treatment of mice with LDN significantly inhibited the Ang II-induced activation of AKT, ERK1/2, HIF-1α, TGF-β/Smad2/3, IL-1, IL-6, and NOX, thereby leading to the improvement of atrial remodeling and AF (Figs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice

Zhang

Yang

et al. 2019

Hypertens Res

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Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.

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“…NSC632839 is another inhibitor that affects UCH-L1 activity. However, NSC632839 activity is not specific to UCH-L1, and it is already known to inhibit USP2 and USP7 [ 178 , 179 ]. The amount of p62 in cells is reduced after treatment with both LDN-57444 and NCS632839, suggesting that these drugs could prevent the accumulation of protein aggregates [ 178 ].…”

Section: Targeting Deubiquitinating Enzymes Acting In Autophagy Fomentioning

confidence: 99%

Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?

Jacomin

Taillebourg

Fauvarque

2018

Cells

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Autophagy is an evolutionary conserved catabolic process that allows for the degradation of intracellular components by lysosomes. This process can be triggered by nutrient deprivation, microbial infections or other challenges to promote cell survival under these stressed conditions. However, basal levels of autophagy are also crucial for the maintenance of proper cellular homeostasis by ensuring the selective removal of protein aggregates and dysfunctional organelles. A tight regulation of this process is essential for cellular survival and organismal health. Indeed, deregulation of autophagy is associated with a broad range of pathologies such as neuronal degeneration, inflammatory diseases, and cancer progression. Ubiquitination and deubiquitination of autophagy substrates, as well as components of the autophagic machinery, are critical regulatory mechanisms of autophagy. Here, we review the main evidence implicating deubiquitinating enzymes (DUBs) in the regulation of autophagy. We also discuss how they may constitute new therapeutic opportunities in the treatment of pathologies such as cancers, neurodegenerative diseases or infections.

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Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity

Cited by 22 publications

References 35 publications

Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Preclinical Comparison of Stem Cells Secretome and Levodopa Application in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease

Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice

Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?

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