Inhibiting the Deubiquitinase UCHL1 Reduces SARS-CoV-2 Viral Uptake by ACE2 DOI Creative Commons
Joseph S. Bednash, Finny Johns, Daniela Farkas

и другие.

American Journal of Respiratory Cell and Molecular Biology, Год журнала: 2023, Номер 68(5), С. 566 - 576

Опубликована: Фев. 2, 2023

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) remains a significant public health burden with limited treatment options. Many beta-coronaviruses, including SARS-CoV-2, gain entry to host cells through interaction of Spike (S) protein membrane-bound angiotensin-converting enzyme 2 (ACE2). Given its necessity for infection, ACE2 represents potential therapeutic target in COVID-19. However, early attempts focusing on have not validated it as druggable nor identified other ACE2-related novel proteins intervention. Here, we identify mechanism modulation the deubiquitinase (DUB) enzyme, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). is constitutively ubiquitinated and degraded proteasome lung epithelia. spike cellular internalization increased abundance decreasing degradation. Using an siRNA library targeting 96 human DUBs, UCHL1 putative regulator function viral receptor. Overexpressed preserved abundance, whereas silencing DUB destabilized polyubiquitination. A commercially available small molecule inhibitor activity decreased levels coupled inhibition infection epithelial cells. These findings describe unique pathway regulation uncovering modulate platform future design testing. This article open access distributed under terms Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Язык: Английский

AMPK and NRF2: Interactive players in the same team for cellular homeostasis? DOI Creative Commons

Eleni Petsouki,

Shara Natalia Sosa Cabrera,

Elke H. Heiß

и другие.

Free Radical Biology and Medicine, Год журнала: 2022, Номер 190, С. 75 - 93

Опубликована: Июль 31, 2022

NRF2 (Nuclear factor E2 p45‐related 2) is a stress responsive transcription lending cells resilience against oxidative, xenobiotic, and also nutrient or proteotoxic insults. AMPK (AMP-activated kinase), considered as prime regulator of cellular energy homeostasis, not only tunes metabolism to provide the cell at any time with sufficient ATP building blocks, but controls redox balance inflammation. Due observed overlapping responses upon activation common stressors impinging on both signaling, it plausible assume that signaling may interdepend cooperate readjust homeostasis. After short introduction two players this narrative review paints current picture how might interact molecular level, highlights their possible crosstalk in selected examples pathophysiology bioactivity drugs phytochemicals.

Язык: Английский

Процитировано

76
Recent Advances in Small Molecule Inhibitors of Deubiquitinating Enzymes DOI

Pengwei Liu,

Zhengyang Chen,

Yiting Guo

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117324 - 117324

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

4
Ubiquitin and Ubiquitin-like Proteins in Cancer, Neurodegenerative Disorders, and Heart Diseases DOI Open Access
Jin‐Taek Hwang, Ah Young Lee, Changwon Kho

и другие.

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(9), С. 5053 - 5053

Опубликована: Май 2, 2022

Post-translational modification (PTM) is an essential mechanism for enhancing the functional diversity of proteins and adjusting their signaling networks. The reversible conjugation ubiquitin (Ub) ubiquitin-like (Ubls) to cellular among most prevalent PTM, which modulates various physiological processes by altering activity, stability, localization, trafficking, or interaction networks its target molecules. Ub/Ubl tightly regulated as a multi-step enzymatic process enzymes specific this family. There growing evidence that dysregulation modifications associated with diseases, providing new targets drug development. In review, we summarize recent progress in understanding roles therapeutic Ub Ubl systems onset progression human including cancer, neurodegenerative disorders, heart diseases.

Язык: Английский

Процитировано

45
Exploring the Role of Ubiquitin–Proteasome System in Parkinson's Disease DOI
Tapan Behl, Sachin Kumar, Ziyad M. Althafar

и другие.

Molecular Neurobiology, Год журнала: 2022, Номер 59(7), С. 4257 - 4273

Опубликована: Май 3, 2022

Язык: Английский

Процитировано

41
Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia DOI
Zhu Liang, Andreas Damianou, Iolanda Vendrell

и другие.

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114152 - 114152

Опубликована: Апрель 25, 2024

Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 assembly activation are controlled, in particular by components ubiquitin system, proximity labeling, affinity purification, RNAi screening approaches were performed. Our study provides intricate time-resolved molecular map different phases activation. Also, we show that C-terminal hydrolase 1 (UCH-L1) interacts with NACHT domain NLRP3. Downregulation UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. chemical inhibition small molecules interfered puncta formation ASC oligomerization, leading to altered IL-1β cleavage secretion, particularly microglia cells, which exhibited elevated expression as compared monocytes/macrophages. Altogether, profiled dynamics highlight important modulator NLRP3-mediated production, suggesting a pharmacological inhibitor may decrease inflammation-associated pathologies.

Язык: Английский

Процитировано

11
Deubiquitinase UCHL1 promotes angiogenesis and blood–spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17 DOI Creative Commons
Jiaxing Wang,

Chengyue Ji,

Wu Ye

и другие.

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Март 13, 2024

Abstract Improving the function of blood–spinal cord barrier (BSCB) benefits functional recovery mice following spinal injury (SCI). The death endothelial cells and disruption BSCB at site contribute to secondary damage, ubiquitin–proteasome system is involved in regulating protein function. However, little known about regulation deubiquitinated enzymes their effect on after SCI. We observed that Sox17 predominantly localized significantly upregulated SCI LPS-treated brain microvascular cells. In vitro knockdown attenuated cell proliferation, migration, tube formation, while vivo inhibited regeneration recovery, leading poor Conversely, overexpression promoted angiogenesis injury. Additionally, immunoprecipitation-mass spectrometry revealed interaction between deubiquitinase UCHL1 Sox17, which stabilized influenced repair By generating conditional knockout conducting rescue experiments, we further validated promotes restoration by stabilizing Sox17. Collectively, our findings present a novel therapeutic target for treating revealing potential mechanism

Язык: Английский

Процитировано

10
A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson’s disease DOI Creative Commons

Lijun Dou,

Zhenxing Xu,

Jielin Xu

и другие.

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 22, 2025

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack ability to slow or prevent progression. We utilized a systems genetics approach identify potential risk genes repurposable drugs for PD. First, we leveraged non-coding genome-wide association studies (GWAS) loci effects on five types of brain-specific quantitative trait (xQTLs, including expression, protein, splicing, methylation histone acetylation) under protein–protein interactome (PPI) network. then prioritized 175 PD likely (pdRGs), such as SNCA, CTSB, LRRK2, DGKQ, CD44, which are enriched in druggable targets differentially expressed across multiple human cell types. Integrating network proximity-based drug repurposing patient electronic health record (EHR) data observations, identified Simvastatin being significantly associated with reduced incidence (hazard ratio (HR) = 0.91 fall outcome, 95% confidence interval (CI): 0.87–0.94; HR 0.88 dementia CI: 0.86–0.89) after adjusting 267 covariates. In summary, our network-based framework identifies other diseases if broadly applied.

Язык: Английский

Процитировано

1
UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis DOI
Lu Lin, S. Li,

S. Hu

и другие.

Journal of Dental Research, Год журнала: 2022, Номер 102(1), С. 61 - 71

Опубликована: Сен. 12, 2022

Periodontitis comprises a series of inflammatory responses resulting in alveolar bone loss. The suppression osteogenesis periodontal ligament stem cells (PDLSCs) by inflammation is responsible for impaired regeneration, which remains an ongoing challenge periodontitis therapy. Ubiquitin C-terminal hydrolase L1 (UCHL1) belongs to the family deubiquitinating enzymes, was found play roles previously. In this study, upregulation UCHL1 identified inflamed PDLSCs isolated from patients and healthy treated with tumor necrosis factor–α or interleukin–1β, higher expression level accompanied PDLSCs. Then inhibited using lentivirus inhibitor, suppressed rescued inhibition. Mechanistically, negative effect on attributable its regulation mitophagy-dependent morphogenetic protein 2/Smad signaling pathway periodontitis-associated inflammation. Furthermore, ligature-induced murine model established, specific inhibitor administrated mice. histological results showed increased active osteoblasts surface enhanced regeneration when Besides, therapeutic effects inhibition ameliorating were verified, as indicated less loss reduced Altogether, our study proved be key regulator suggested that holds promise treatment.

Язык: Английский

Процитировано

29
PINK1 and Parkin regulate IP3R-mediated ER calcium release DOI Creative Commons
Su Jin Ham, Heesuk Yoo, Daihn Woo

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 25, 2023

Although defects in intracellular calcium homeostasis are known to play a role the pathogenesis of Parkinson's disease (PD), underlying molecular mechanisms remain unclear. Here, we show that loss PTEN-induced kinase 1 (PINK1) and Parkin leads dysregulation inositol 1,4,5-trisphosphate receptor (IP

Язык: Английский

Процитировано

21
The Role of Ubiquitin–Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease DOI
Liang Yú,

Guangshang Zhong,

Mingxin Ren

и другие.

NeuroMolecular Medicine, Год журнала: 2023, Номер 25(4), С. 471 - 488

Опубликована: Сен. 12, 2023

Язык: Английский

Процитировано

18