Deubiquitylating enzymes: potential target in autoimmune diseases

Parihar, Niraj; Bhatt, Lokesh Kumar

doi:10.1007/s10787-021-00890-z

Cited by 10 publications

(3 citation statements)

References 157 publications

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“…The ubiquitin-proteasome pathway regulates a series of critical cellular functions, including differentiation, proliferation, and apoptosis. Changes in this pathway may lead to developmental abnormalities, autoimmune diseases, neurodegenerative diseases, and cancer [27,28]. Similarly, the autophagylysosome pathway can be significantly upregulated by many cell stressors and diseases [29].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

Liu

et al. 2022

IJMS

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Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer’s disease (AD), glioma, cancer, etc. Our previous work has reported its interaction with the catalytic subunit of gamma-secretase, PS1, and it regulates the activity of PS1 via transferring it from the early endosome to the late endosome/lysosome. However, it is still unknown how Rab21 protein itself is regulated. This work revealed that Rab21 protein, either endogenously or exogenously, can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. It is further observed that the ubiquitinated Rab21 is increased, but the total protein is unchanged in AD model mice. We further observed that overexpression of Rab21 leads to increased expression of a series of genes involved in the autophagy-lysosome pathway. We speculated that even though the ubiquitinated Rab21 is increased due to the impaired proteasome function in the AD model, the autophagy-lysosome pathway functions in parallel to degrade Rab21 to keep its protein level in homeostasis. In conclusion, understanding the characters of Rab21 protein itself help explore its potential as a target for therapeutic strategy in diseases.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

Liu

et al. 2022

IJMS

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“…Among these DUBs, USPs are the largest family to cleave ubiquitin from substrates. Dysregulation of USPs have been implicated in various diseases, such as neurodegeneration, inflammation and cancer (30)(31)(32). It is clear that the balance between ubiquitination and deubiquitination is pivotal for maintaining proper protein levels and their functions (33).…”

Section: Introductionmentioning

confidence: 99%

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

Zheng

Chen

et al. 2023

Front. Immunol.

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Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type of post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression of osteoarthritis via targeting specific proteins for ubiquitination and determining protein stability and localization. Ubiquitination process can be reversed by a class of deubiquitinases via deubiquitination. In this review, we summarize the current knowledge regarding the multifaceted role of E3 ubiquitin ligases in the pathogenesis of osteoarthritis. We also describe the molecular insight of deubiquitinases into osteoarthritis processes. Moreover, we highlight the multiple compounds that target E3 ubiquitin ligases or deubiquitinases to influence osteoarthritis progression. We discuss the challenge and future perspectives via modulation of E3 ubiquitin ligases and deubiquitinases expression for enhancement of the therapeutic efficacy in osteoarthritis patients. We conclude that modulating ubiquitination and deubiquitination could alleviate the osteoarthritis pathogenesis to achieve the better treatment outcomes in osteoarthritis patients.

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“…Deubiquitinating enzymes (DUBs) remove single or poly-ubiquitin from proteins marked for proteasomal degradation, thus prolonging their biological effects. − Ubiquitin-specific protease 7 (USP7) is a DUB enzyme that plays important roles in cell stress response, viral response, the immune response, transcription regulation, tumor suppression, cell cycle control, and apoptosis (Figure C). , Due to the ubiquitous expression of USP7, its association with viral infection, and the observation that aberrant activation or overexpression of USP7 may promote oncogenesis, USP7 has become an attractive therapeutic target and a number of small-molecule inhibitors have been described. ,, Recently, a novel protein-based USP7 inhibitor, UbV.7.2, was developed using a phage-display approach. − To the best of our knowledge, this biologic has the highest selectivity and inhibitory potency of all USP7 inhibitors reported to date (IC 50 = 16.2 nM) . Transfection of HEK293T cells with a UbV.7.2 expression vector results in a significant decrease in mouse double minute 2 homolog (MDM2) levels and stabilization of p53 levels, presumably due to USP7 inhibition .…”

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confidence: 99%

A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells

et al. 2022

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Biological therapeutics represent an increasing and critical component of newly approved drugs; however, the inability to deliver biologics intracellularly in a controlled manner remains a major limitation. We have developed a semi-synthetic, tunable phage-like particle (PLP) platform derived from bacteriophage λ. The shell surface can be decorated with small-molecule, biological and synthetic moieties, alone or in combination and in defined ratios. Here, we demonstrate that the platform can be used to deliver biological macromolecules intracellularly and in a controlled manner. Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that has been widely recognized as an ideal target for the treatment of a variety of cancers. Recently, UbV.7.2, a novel biologic derived from the ubiquitin scaffold, was developed for inhibition of USP7, but issues remain in achieving efficient and controlled intracellular delivery of the biologic. We have shown that decoration of PLPs with trastuzumab (Trz), a HER2-targeted therapeutic used in the treatment of various cancers, results in specific targeting and uptake of Trz-PLPs into HER2-overexpressing breast cancer cells. By simultaneously decorating PLPs with Trz and UbV.7.2, we now show that these particles are also internalized by HER2-positive cells, thus providing a means for intracellular delivery of the biologic in a controlled fashion. Internalized particles retain USP7 inhibition activity of UbV.7.2 and alter the metabolic and proteomic landscapes of these cells. This study demonstrates that the λ "designer nanoparticles" represent a powerful system for the intracellular delivery of biologics in a defined dose.

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Deubiquitylating enzymes: potential target in autoimmune diseases

Cited by 10 publications

References 157 publications

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

A Designer Nanoparticle Platform for Controlled Intracellular Delivery of Bioactive Macromolecules: Inhibition of Ubiquitin-Specific Protease 7 in Breast Cancer Cells

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