scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals The structure and function of deubiquitinases: lessons from budding yeast

Open Biology ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 200279
Author(s):  
Harsha Garadi Suresh ◽  
Natasha Pascoe ◽  
Brenda Andrews
Keyword(s):  
Protein Quality ◽  
Budding Yeast ◽  
Post Translational Modification ◽  
Repair Gene ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
The Many ◽  
Key Aspects ◽  
And Function

Protein ubiquitination is a key post-translational modification that regulates diverse cellular processes in eukaryotic cells. The specificity of ubiquitin (Ub) signalling for different bioprocesses and pathways is dictated by the large variety of mono-ubiquitination and polyubiquitination events, including many possible chain architectures. Deubiquitinases (DUBs) reverse or edit Ub signals with high sophistication and specificity, forming an integral arm of the Ub signalling machinery, thus impinging on fundamental cellular processes including DNA damage repair, gene expression, protein quality control and organellar integrity. In this review, we discuss the many layers of DUB function and regulation, with a focus on insights gained from budding yeast. Our review provides a framework to understand key aspects of DUB biology.

scholarly journals TIP60 governs the auto-ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

2020 ◽  
Author(s):  
Tanveer Ahmad ◽  
Waseem Ashraf ◽  
Abdulkhaleg Ibrahim ◽  
Liliyana Zaayter ◽  
Christian D. Muller ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Ring Finger ◽  
Fluorescence Lifetime Imaging ◽  
Cellular Functions ◽  
Apoptotic Pathway ◽  
Cellular Processes ◽  
Lifetime Imaging ◽  
Damage Repair ◽  
Microscopy Techniques

Abstract Background: The epigenetic regulator UHRF1 (Ubiquitin-like, containing PHD and RING finger domains 1) plays an essential role in faithful transmission of DNA methylation during replication. It has tumorogenesis potential and is overexpressed in cancers. TIP60 (Tat interactive protein, 60 kDa) is an important partner of UHRF1, ensuring various cellular processes through its acetyltransferase activity. TIP60 is believed to exert a tumor suppressive role partly explained by its down-regulation in many cancers. Both proteins participate in various cellular functions such as chromatin remodeling, cell cycle, DNA damage repair and regulation of protein stability.Methods: Immunoprecipitation and confocal microscopy techniques were performed to study the ubiquitination of UHRF1 and USP-UHRF1 association. Fluorescence lifetime imaging microscopy (FLIM) technique was performed to analyze the interaction between UHRF1 and ubiquitin inside the nucleus. Western blotting was used to assess the effect of TIP60 overexpression on p73, pro- and anti-apoptotic proteins. TIP60-mediated apoptosis in HeLa cells was investigated by flow cytometry. Results were statistically analyzed using Graphpad prism.Results: Herein, our goal was to investigate the role and mechanism of TIP60 in the regulation of UHRF1 expression. Our results showed that TIP60 overexpression down-regulated UHRF1 and DNMT1 (DNA methyltransferase 1) expressions. TIP60 interfered with USP7-UHRF1 association and induced degradation of UHRF1 in an auto-ubiquitination dependent pathway. Moreover, TIP60 activated the p73-mediated apoptotic pathway.Conclusion: Taken together, our data suggest that the tumor suppressor role of TIP60 is mediated by its regulation to UHRF1.

scholarly journals The Role of Deubiquitinases in Oncovirus and Host Interactions

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yueshuo Li ◽  
Feng Shi ◽  
Jianmin Hu ◽  
Longlong Xie ◽  
Ann M. Bode ◽  
...  
Keyword(s):  
Life Cycle ◽  
Signaling Pathways ◽  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Antiviral Signaling ◽  
Host Interactions ◽  
Cellular Processes ◽  
Ubiquitin System ◽  
Almost All

Infection-related cancer comprises one-sixth of the global cancer burden. Oncoviruses can directly or indirectly contribute to tumorigenesis. Ubiquitination is a dynamic and reversible posttranslational modification that participates in almost all cellular processes. Hijacking of the ubiquitin system by viruses continues to emerge as a central theme around the viral life cycle. Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling pathways, as well as acting as key mediators between the virus and its host. In this review, we focus on the multiple functions of DUBs in RIG-I-like receptors (RLRs) and stimulator of interferon genes (STING)-mediated antiviral signaling pathways, oncoviruses regulation of NF-κB activation, oncoviral life cycle, and the potential of DUB inhibitors as therapeutic strategies.

scholarly journals The Antiviral Activities of Poly-ADP-Ribose Polymerases

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 582
Author(s):  
Mathilde Malgras ◽  
Magali Garcia ◽  
Clément Jousselin ◽  
Charles Bodet ◽  
Nicolas Lévêque
Keyword(s):  
Antiviral Activity ◽  
Chromatin Remodeling ◽  
Adenosine Diphosphate ◽  
Innate Immune ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Damage Repair ◽  
Antiviral Activities ◽  
Virus Replication Cycle

The poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) are responsible for ADP-ribosylation, a reversible post-translational modification involved in many cellular processes including DNA damage repair, chromatin remodeling, regulation of translation and cell death. In addition to these physiological functions, recent studies have highlighted the role of PARPs in host defenses against viruses, either by direct antiviral activity, targeting certain steps of virus replication cycle, or indirect antiviral activity, via modulation of the innate immune response. This review focuses on the antiviral activity of PARPs, as well as strategies developed by viruses to escape their action.

scholarly journals Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

scholarly journals Targeting Hedgehog Signalling through the Ubiquitylation Process: The Multiple Roles of the HECT-E3 Ligase Itch

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 98 ◽  
Author(s):  
Paola Infante ◽  
Ludovica Lospinoso Severini ◽  
Flavia Bernardi ◽  
Francesca Bufalieri ◽  
Lucia Di Marcotullio
Keyword(s):  
E3 Ligase ◽  
Multiple Roles ◽  
Post Translational Modification ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Promising Target ◽  
Important Pathway ◽  
Multiple Levels

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.

scholarly journals Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization in Drosophila

2005 ◽  
Vol 16 (7) ◽  
pp. 3107-3116 ◽  
Author(s):  
Anindya Ghosh-Roy ◽  
Bela S. Desai ◽  
Krishanu Ray
Keyword(s):  
Light Chain ◽  
Cytoplasmic Dynein ◽  
Actin Dynamics ◽  
Dynein Light Chain ◽  
Actin Assembly ◽  
Cellular Functions ◽  
Directed Movement ◽  
Cellular Processes ◽  
Dynactin Complex

Toward the end of spermiogenesis, spermatid nuclei are compacted and the clonally related spermatids individualize to become mature and active sperm. Studies in Drosophila showed that caudal end-directed movement of a microfilament-rich structure, called investment cone, expels the cytoplasmic contents of individual spermatids. F-actin dynamics plays an important role in this process. Here we report that the dynein light chain 1 (DLC1) of Drosophila is involved in two separate cellular processes during sperm individualization. It is enriched around spermatid nuclei during postelongation stages and plays an important role in the dynein-dynactin–dependent rostral retention of the nuclei during this period. In addition, DDLC1 colocalizes with dynamin along investment cones and regulates F-actin assembly at this organelle by retaining dynamin along the cones. Interestingly, we found that this process does not require the other subunits of cytoplasmic dynein-dynactin complex. Altogether, these observations suggest that DLC1 could independently regulate multiple cellular functions and established a novel role of this protein in F-actin assembly in Drosophila.

Functional analysis of the SUMOylation pathway in Drosophila

2008 ◽  
Vol 36 (5) ◽  
pp. 868-873 ◽  
Author(s):  
Ana Talamillo ◽  
Jonatan Sánchez ◽  
Rosa Barrio
Keyword(s):  
Functional Analysis ◽  
Fine Tuning ◽  
Model Systems ◽  
Post Translational Modification ◽  
Reversible Process ◽  
Cellular Processes ◽  
Tuning Mechanism ◽  
Sumo Conjugation

SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

scholarly journals A Human DUB Protein Array for Clarification of Linkage Specificity of Polyubiquitin Chain and Application to Evaluation of Its Inhibitors

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 152
Author(s):  
Hirotaka Takahashi ◽  
Satoshi Yamanaka ◽  
Shohei Kuwada ◽  
Kana Higaki ◽  
Kohki Kido ◽  
...  
Keyword(s):  
Drug Targets ◽  
Protein Array ◽  
Polyubiquitin Chain ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Model Study ◽  
Biochemical Analyses ◽  
Almost All

Protein ubiquitinations play pivotal roles in many cellular processes, including homeostasis, responses to various stimulations, and progression of diseases. Deubiquitinating enzymes (DUBs) remove ubiquitin molecules from ubiquitinated proteins and cleave the polyubiquitin chain, thus negatively regulating numerous ubiquitin-dependent processes. Dysfunctions of many DUBs reportedly cause various diseases; therefore, DUBs are considered as important drug targets, although the biochemical characteristics and cellular functions of many DUBs are still unclear. Here, we established a human DUB protein array to detect the activity and linkage specificity of almost all human DUBs. Using a wheat cell-free protein synthesis system, 88 full-length recombinant human DUB proteins were prepared and termed the DUB array. In vitro DUB assays were performed with all of these recombinant DUBs, using eight linkage types of diubiquitins as substrates. As a result, 80 DUBs in the array showed DUB activities, and their linkage specificities were determined. These 80 DUBs included many biochemically uncharacterized DUBs in the past. In addition, taking advantage of these active DUB proteins, we applied the DUB array to evaluate the selectivities of DUB inhibitors. We successfully developed a high-throughput and semi-quantitative DUB assay based on AlphaScreen technology, and a model study using two commercially available DUB inhibitors revealed individual selectivities to 29 DUBs, as previously reported. In conclusion, the DUB array established here is a powerful tool for biochemical analyses and drug discovery for human DUBs.

scholarly journals FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression

2019 ◽  
Vol 68 (3) ◽  
pp. 786-791 ◽  
Author(s):  
Ban Wang ◽  
Yanhui Li ◽  
Heather Wang ◽  
Jing Zhao ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Half Life ◽  
Transforming Growth Factor ◽  
Fibroblast Cells ◽  
Post Translational Modification ◽  
Human Lung Fibroblast ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Fibronectin Expression ◽  
Tgf Β1

FOXO3a belongs to a family of transcription factors characterized by a conserved forkhead box DNA-binding domain. It has been known to regulate various cellular processes including cell proliferation, apoptosis and differentiation. Post-translational modifications of FOXO3a and their roles in the regulation of FOXO3a activity have been well-documented. FOXO3a can be phosphorylated, acetylated and ubiquitinated, however, the ISGylation of FOXO3a has not been reported. Protein overexpression, ISGylation and half-life were measured to determine the post-translational modification of FOXO3a. Human fibroblast cells were treated with transforming growth factor (TGF)-β1 to determine the role of FOXO3a ISGylation in TGF-β1 signaling. FOXO3a’s half-life is around 3.7 hours. Inhibition of the proteasome, not lysosome, extends its half-life. ISGylation, but not ubiquitination of FOXO3a, is increased in the presence of the proteasome inhibitor. Overexpression of ISG15 increases FOXO3a degradation, while overexpression of USP18 stabilizes FOXO3a through de-ISGylation. These results suggest that FOXO3a is degraded in the ISGylation and proteasome system, which can be reversed by USP18, an ISG15-specific deubiquitinase. This study reveals a new molecular mechanism by which ISGylation regulates FOXO3a degradation. Furthermore, we show that the overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in human lung fibroblast cells without altering Smad2/3 expression and activation. FOXO3a can be ISGylated, which can regulate FOXO3a stability. USP18/FOXO3a pathway is a potential target for treating TGF-β1-mediated fibrotic diseases such as idiopathic pulmonary fibrosis.

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