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Cells
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The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation
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The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 14644

Special Issue Editor

Dr. Bernat Crosas

E-Mail Website
Guest Editor
Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona Science Park, 08028 Barcelona, Spain
Interests: proteasome; ubiquitin; proteolytic chimeras; targeted protein degradation; bispecific and multi-specific degraders

Special Issue Information

Dear Colleagues,

This Special Issue of Cells on “The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation” offers scholars the opportunity to publish research articles and reviews on proximity-based chimeras and molecular glues, one of the most expanding fields in innovative therapies. This Special Issue envisions the mechanistic basis of targeted protein degradation, placing the focus, not only on the main actors in UPS, ubiquitin ligases, but also on other key regulators such as deubiquitinating enzymes, adaptor proteins and all the factors that make the UPS one of the most complex systems in cells. Beyond that, we are interested in all proximity-based approaches that focus on highly specific therapeutic strategies, linked to targeted protein degradation. Chimeras directed towards autophagy or endocytic internalization for lysosomal degradation, novel biorthogonal approaches, innovative bispecific and multi-specific strategies are also welcome in the Special Issue.  We look forward to your contributions!

Dr. Bernat Crosas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ubiquitin–proteasome system
  • ubiquitin ligases
  • targeted protein degradation
  • bispecific chimeras
  • novel chimera approaches

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Published Papers (6 papers)

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Research

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14 pages, 2219 KiB  
Article
Aptamer-Hytac Chimeras for Targeted Degradation of SARS-CoV-2 Spike-1
by Carme Fàbrega, Núria Gallisà-Suñé, Alice Zuin, Juan Sebastián Ruíz, Bernat Coll-Martínez, Gemma Fabriàs, Ramon Eritja and Bernat Crosas
Cells 2024, 13(21), 1767; https://doi.org/10.3390/cells13211767 - 25 Oct 2024
Cited by 1 | Viewed by 1071
Abstract
The development of novel tools to tackle viral processes has become a central focus in global health, during the COVID-19 pandemic. The spike protein is currently one of the main SARS-CoV-2 targets, owing to its key roles in infectivity and virion formation. In [...] Read more.
The development of novel tools to tackle viral processes has become a central focus in global health, during the COVID-19 pandemic. The spike protein is currently one of the main SARS-CoV-2 targets, owing to its key roles in infectivity and virion formation. In this context, exploring innovative strategies to block the activity of essential factors of SARS-CoV-2, such as spike proteins, will strengthen the capacity to respond to current and future threats. In the present work, we developed and tested novel bispecific molecules that encompass: (i) oligonucleotide aptamers S901 and S702, which bind to the spike protein through its S1 domain, and (ii) hydrophobic tags, such as adamantane and tert-butyl-carbamate-based ligands. Hydrophobic tags have the capacity to trigger the degradation of targets recruited in the context of a proteolytic chimera by activating quality control pathways. We observed that S901-adamantyl conjugates promote the degradation of the S1 spike domain, stably expressed in human cells by genomic insertion. These results highlight the suitability of aptamers as target-recognition molecules and the robustness of protein quality control pathways triggered by hydrophobic signals, and place aptamer-Hytacs as promising tools for counteracting coronavirus progression in human cells. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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24 pages, 3809 KiB  
Article
The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway
by Tomasz Uśpieński and Paweł Niewiadomski
Cells 2024, 13(17), 1496; https://doi.org/10.3390/cells13171496 - 6 Sep 2024
Viewed by 1367
Abstract
Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal [...] Read more.
Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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15 pages, 3366 KiB  
Article
Diallyl Trisulfide Causes Male Infertility with Oligoasthenoteratospermia in Sitotroga cerealella through the Ubiquitin–Proteasome Pathway
by Sakhawat Shah, Karam Khamis Elgizawy, Meng-Ya Wu, Hucheng Yao, Wen-Han Yan, Yu Li, Xiao-Ping Wang, Gang Wu and Feng-Lian Yang
Cells 2023, 12(20), 2507; https://doi.org/10.3390/cells12202507 - 23 Oct 2023
Cited by 1 | Viewed by 1629
Abstract
Essential oils extracted from plant sources along with their biologically active components may have negative effects on insects. Diallyl trisulfide (DAT) is an active component of garlic essential oil, and it exhibits multi-targeted activity against many organisms. Previously we reported that DAT induces [...] Read more.
Essential oils extracted from plant sources along with their biologically active components may have negative effects on insects. Diallyl trisulfide (DAT) is an active component of garlic essential oil, and it exhibits multi-targeted activity against many organisms. Previously we reported that DAT induces male infertility and leads to apyrene and eupyrene sperm dysfunction in Sitotroga cerealella. In this study, we conducted an analysis of testis-specific RNA-Seq data and identified 449 downregulated genes and 60 upregulated genes in the DAT group compared to the control group. The downregulated genes were significantly enriched in the ubiquitin–proteasome pathway. Furthermore, DAT caused a significant reduction in mRNA expression of proteasome regulatory subunit particles required for ATP-dependent degradation of ubiquitinated proteins as well as decreased the expression profile of proteasome core particles, including β1, β2, and β5. Sperm physiological analysis showed that DAT decreased the chymotrypsin-like activity of the 20S proteasome and formed aggresomes in spermatozoa. Overall, our findings suggest that DAT impairs the testis proteasome, ultimately causing male infertility characterized by oligoasthenoteratospermia due to disruption in sperm proteasome assembly in S. cerealella. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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Review

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37 pages, 1133 KiB  
Review
Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities
by Aiman B. Awan, Maryiam Jama Ali Osman and Omar M. Khan
Cells 2025, 14(2), 69; https://doi.org/10.3390/cells14020069 - 7 Jan 2025
Cited by 1 | Viewed by 1774
Abstract
Ubiquitination is cells’ second most abundant posttranslational protein modification after phosphorylation. The ubiquitin–proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development [...] Read more.
Ubiquitination is cells’ second most abundant posttranslational protein modification after phosphorylation. The ubiquitin–proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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24 pages, 3174 KiB  
Review
Unraveling the Role of Ubiquitin-Conjugating Enzyme UBE2T in Tumorigenesis: A Comprehensive Review
by Chang Gao, Yan-Jun Liu, Jing Yu, Ran Wang, Jin-Jin Shi, Ru-Yi Chen, Guan-Jun Yang and Jiong Chen
Cells 2025, 14(1), 15; https://doi.org/10.3390/cells14010015 - 26 Dec 2024
Cited by 3 | Viewed by 1521
Abstract
Ubiquitin-conjugating enzyme E2 T (UBE2T) is a crucial E2 enzyme in the ubiquitin-proteasome system (UPS), playing a significant role in the ubiquitination of proteins and influencing a wide range of cellular processes, including proliferation, differentiation, apoptosis, invasion, and metabolism. Its overexpression has been [...] Read more.
Ubiquitin-conjugating enzyme E2 T (UBE2T) is a crucial E2 enzyme in the ubiquitin-proteasome system (UPS), playing a significant role in the ubiquitination of proteins and influencing a wide range of cellular processes, including proliferation, differentiation, apoptosis, invasion, and metabolism. Its overexpression has been implicated in various malignancies, such as lung adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, and ovarian cancer, where it correlates strongly with disease progression. UBE2T facilitates tumorigenesis and malignant behaviors by mediating essential functions such as DNA repair, apoptosis, cell cycle regulation, and the activation of oncogenic signaling pathways. High levels of UBE2T expression are associated with poor survival outcomes, highlighting its potential as a molecular biomarker for cancer prognosis. Increasing evidence suggests that UBE2T acts as an oncogene and could serve as a promising therapeutic target in cancer treatment. This review aims to provide a detailed overview of UBE2T’s structure, functions, and molecular mechanisms involved in cancer progression as well as recent developments in UBE2T-targeted inhibitors. Such insights may pave the way for novel strategies in cancer diagnosis and treatment, enhancing our understanding of UBE2T’s role in cancer biology and supporting the development of innovative therapeutic approaches. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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37 pages, 1892 KiB  
Review
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders
by Corentin Bouvier, Rachel Lawrence, Francesca Cavallo, Wendy Xolalpa, Allan Jordan, Roland Hjerpe and Manuel S. Rodriguez
Cells 2024, 13(7), 578; https://doi.org/10.3390/cells13070578 - 26 Mar 2024
Cited by 9 | Viewed by 6207
Abstract
Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several [...] Read more.
Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease. Full article
(This article belongs to the Special Issue The Ubiquitin–Proteasome System (UPS): Signaling Processes and Targeted Protein Degradation)
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