-
Cell Death and Differentiation Sep 2022MYC as a transcriptional factor plays a crucial role in breast cancer progression. However, the mechanisms underlying MYC deubiquitination in breast cancer are not well...
MYC as a transcriptional factor plays a crucial role in breast cancer progression. However, the mechanisms underlying MYC deubiquitination in breast cancer are not well defined. Here, we report that OTUB1 is responsible for MYC deubiquitination. OTUB1 could directly deubiquitinate MYC at K323 site, which blocks MYC protein degradation. Moreover, OTUB1 mediated MYC protein stability is also confirmed in OTUB1-knockout mice. Stabilized MYC by OTUB1 promotes its transcriptional activity and induces HK2 expression, which leads to enhance aerobic glycolysis. Therefore, OTUB1 promotes breast tumorigenesis in vivo and in vitro via blocking MYC protein degradation. Taken together, our data identify OTUB1 as a new deubiquitination enzyme for MYC protein degradation, which provides a potential target for breast cancer treatment.
Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Cysteine Endopeptidases; Deubiquitinating Enzymes; Glycolysis; Mice; Ubiquitination
PubMed: 35296795
DOI: 10.1038/s41418-022-00971-8 -
International Journal of Molecular... May 2020Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight... (Review)
Review
Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host's immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.
Topics: Animals; Betacoronavirus; COVID-19; Coronavirus; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Deubiquitinating Enzymes; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32429099
DOI: 10.3390/ijms21103492 -
Trends in Cancer Oct 2019Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes... (Review)
Review
Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes and can be opposed by deubiquitinases (DUBs), which have emerged as promising drug targets. Apart from protein localization and activity, ubiquitylation regulates degradation of proteins, among them hypoxia-inducible factors (HIFs). Thereby, various E3 ubiquitin ligases and DUBs regulate HIF abundance. Conversely, several E3s and DUBs are regulated by hypoxia. While hypoxia is a powerful HIF regulator, less is known about hypoxia-regulated DUBs and their impact on HIFs. Here, we review current knowledge about the relationship of E3s, DUBs, and hypoxia signaling. We also discuss the reciprocal regulation of DUBs by hypoxia and use of DUB-specific drugs in cancer.
Topics: Animals; Deubiquitinating Enzymes; Homeostasis; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Neoplasms; Oxygen; Protein Transport; Proteolysis; Signal Transduction; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31706510
DOI: 10.1016/j.trecan.2019.08.005 -
Cellular & Molecular Immunology Feb 2022The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination processes are closely associated with the occurrence and...
The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation. Ovarian tumor deubiquitinase 1 (OTUD1) is involved in immunoregulatory functions linked to infectious diseases. However, the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease (IBD) remains unclear. Here, we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium (DSS)-induced colitis via excessive release of proinflammatory cytokines. In addition, bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis. Mechanistically, OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator (NEMO). Moreover, the expression of OTUD1 in mucosa samples from ulcerative colitis (UC) patients was lower than that in mucosa samples from healthy controls. Furthermore, we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation. Taken together, our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation, suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.
Topics: Animals; Colitis, Ulcerative; Deubiquitinating Enzymes; Dextran Sulfate; Humans; Inflammation; Inflammatory Bowel Diseases; Mice; NF-kappa B; Receptor-Interacting Protein Serine-Threonine Kinases; Ubiquitin-Specific Proteases
PubMed: 34876703
DOI: 10.1038/s41423-021-00810-9 -
Biomolecules Oct 2022In eukaryotic cells, a large number of proteins are modified by ubiquitination, which leads to proteasomal degradation or change in protein function. The protein... (Review)
Review
In eukaryotic cells, a large number of proteins are modified by ubiquitination, which leads to proteasomal degradation or change in protein function. The protein ubiquitination process can be reversed by a process called deubiquitination, which plays an important regulatory mechanism in cellular control. Deubiquitination is catalyzed by deubiquitinating enzymes (DUBs); the cysteine proteases specifically cleave off ubiquitin from ubiquitinated substrates or ubiquitin precursors. Over the past two decades, components of different DUB families have been found to play important roles in both human and plant pathogenic fungi. Given the importance of DUBs for fungal development and virulence, in this review, we concentrate on recent findings and new insights into the roles of DUBs in different fungal pathogens, with a focus on infection-related morphogenesis and virulence, as well as their roles in development and stress response. We also summarize the DUBs-mediated regulatory mechanisms during the above processes. These findings should allow us to develop novel inhibitors to control fungal pathogens.
Topics: Humans; Ubiquitination; Ubiquitin; Ubiquitins; Deubiquitinating Enzymes; Fungi; Cysteine Proteases
PubMed: 36291632
DOI: 10.3390/biom12101424 -
EMBO Reports Apr 2022Protein ubiquitination is a dynamic and reversible post-translational modification that controls diverse cellular processes in eukaryotes. Ubiquitin-dependent...
Protein ubiquitination is a dynamic and reversible post-translational modification that controls diverse cellular processes in eukaryotes. Ubiquitin-dependent internalization, recycling, and degradation are important mechanisms that regulate the activity and the abundance of plasma membrane (PM)-localized proteins. In plants, although several ubiquitin ligases are implicated in these processes, no deubiquitinating enzymes (DUBs), have been identified that directly remove ubiquitin from membrane proteins and limit their vacuolar degradation. Here, we discover two DUB proteins, UBP12 and UBP13, that directly target the PM-localized brassinosteroid (BR) receptor BR INSENSITIVE1 (BRI1) in Arabidopsis. BRI1 protein abundance is decreased in the ubp12i/ubp13 double mutant that displayed severe growth defects and reduced sensitivity to BRs. UBP13 directly interacts with and effectively removes K63-linked polyubiquitin chains from BRI1, thereby negatively modulating its vacuolar targeting and degradation. Our study reveals that UBP12 and UBP13 play crucial roles in governing BRI1 abundance and BR signaling activity to regulate plant growth.
Topics: Arabidopsis; Arabidopsis Proteins; Brassinosteroids; Deubiquitinating Enzymes; Endopeptidases
PubMed: 35166439
DOI: 10.15252/embr.202153354 -
Nature Communications Apr 2023Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly...
Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.
Topics: Cellular Reprogramming; Deubiquitinating Enzymes; DNA Repair; Embryo, Mammalian; Embryonic Development; Epigenesis, Genetic; Nuclear Transfer Techniques; Animals
PubMed: 37012254
DOI: 10.1038/s41467-023-37576-9 -
Cell Proliferation Aug 2023Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence... (Review)
Review
Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age-related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin-specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in-deep understanding of USPs-mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP-targeted therapeutic strategies for osteoporosis.
Topics: Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 36883930
DOI: 10.1111/cpr.13444 -
Cellular and Molecular Life Sciences :... Feb 2022Although damaged cells can be repaired, cells that are considered unlikely to be repaired are eliminated through apoptosis, a type of predicted cell death found in... (Review)
Review
Although damaged cells can be repaired, cells that are considered unlikely to be repaired are eliminated through apoptosis, a type of predicted cell death found in multicellular organisms. Apoptosis is a structured cell death involving alterations to the cell morphology and internal biochemical changes. This process involves the expansion and cracking of cells, changes in cell membranes, nuclear fragmentation, chromatin condensation, and chromosome cleavage, culminating in the damaged cells being eaten and processed by other cells. The ubiquitin-proteasome system (UPS) is a major cellular pathway that regulates the protein levels through proteasomal degradation. This review proposes that apoptotic proteins are regulated through the UPS and describes a unique direction for cancer treatment by controlling proteasomal degradation of apoptotic proteins, and small molecules targeted to enzymes associated with UPS.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cytochromes c; Deubiquitinating Enzymes; Humans; Mitochondria; Models, Biological; Piperidones; Protease Inhibitors; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 35118522
DOI: 10.1007/s00018-022-04132-5 -
International Journal of Molecular... May 2021Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic... (Review)
Review
Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic diseases and may contribute to their early diagnosis and treatment. The ubiquitin (Ub) system has been shown to play a role in cellular immune response, cellular development, and programmed cell death. Ubiquitination is a post-translational modification that occurs in eukaryotes. Its mechanism involves a number of factors, including Ub-activating enzymes, Ub-conjugating enzymes, and Ub protein ligases. Deubiquitinating enzymes, which are proteases that reversely modify proteins by removing Ub or Ub-like molecules or remodeling Ub chains on target proteins, have recently been regarded as crucial regulators of ubiquitination-mediated degradation and are known to significantly affect cellular pathways, a number of biological processes, DNA damage response, and DNA repair pathways. Research has increasingly shown evidence of the relationship between ubiquitination, deubiquitination, and oral disease. This review investigates recent progress in discoveries in diseased oral sites and discusses the roles of ubiquitination and deubiquitination in oral disease.
Topics: Cracked Tooth Syndrome; Dental Caries; Dentin Sensitivity; Deubiquitinating Enzymes; Forecasting; Gingivitis; Humans; Mouth Diseases; Mouth Neoplasms; Neoplasm Proteins; Periodontal Diseases; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Tooth Diseases; Ubiquitin-Activating Enzymes; Ubiquitinated Proteins; Ubiquitination
PubMed: 34070986
DOI: 10.3390/ijms22115488