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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 -
Trends in Biochemical Sciences Nov 2022The ubiquitin-proteasome system (UPS) is critical for protein quality control and regulating protein lifespans. Following ubiquitination, UPS substrates bind multidomain... (Review)
Review
The ubiquitin-proteasome system (UPS) is critical for protein quality control and regulating protein lifespans. Following ubiquitination, UPS substrates bind multidomain receptors that, in addition to ubiquitin-binding sites, contain functional domains that bind to deubiquitinating enzymes (DUBs) or the E3 ligase E6AP/UBE3A. We provide an overview of the proteasome, focusing on its receptors and DUBs. We highlight the key role of dynamics and importance of the substrate receptors having domains for both binding and processing ubiquitin chains. The UPS is rich with therapeutic opportunities, with proteasome inhibitors used clinically and ongoing development of small molecule proteolysis targeting chimeras (PROTACs) for the degradation of disease-associated proteins. We discuss the therapeutic potential of proteasome receptors, including hRpn13, for which PROTACs have been developed.
Topics: Carrier Proteins; Deubiquitinating Enzymes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteins; Proteolysis; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 35817651
DOI: 10.1016/j.tibs.2022.06.006 -
Frontiers in Immunology 2023Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the... (Review)
Review
Deubiquitinating enzymes (DUBs) are emerging as key factors for the infection of human cells by pathogens such as bacteria and parasites. In this review, we discuss the most recent studies on the role of deubiquitinase activity in exploiting and manipulating ubiquitin (Ub)-dependent host processes during infection. The studies discussed here highlight the importance of DUB host-pathogen research and underscore the therapeutic potential of inhibiting pathogen-specific DUB activity to prevent infectious diseases.
Topics: Animals; Humans; Parasites; Deubiquitinating Enzymes; Ubiquitin; Bacteria
PubMed: 38077335
DOI: 10.3389/fimmu.2023.1303072 -
Oncotarget 2015Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all... (Review)
Review
Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all stable changes to the gene expression process that are not a result of a direct change in the DNA code are described as epigenetics. Epigenetic processes are regulated by post-translational modifications including ubiquitination which can directly affect either histones or transcription factors or may target their co-factors and interacting partners exerting an indirect effect. Deubiquitination of these target proteins is equally important and alterations in this pathway can also lead to cancer development, progression and metastasis. Only the correct, unaltered balance between ubiquitination and deubiquitination ensures healthy cellular homeostasis. In this review we focus on the role of deubiquitinating (DUB) enzymes in various aspects of epigenetics including the regulation of transcription factors, histone modifications, DNA damage repair pathways and cell cycle regulation. We discuss the impact of those processes on tumourigenesis and potential therapeutic applications of DUBs for cancer treatment.
Topics: Animals; Cell Cycle; Chromatin; DNA; DNA Damage; DNA Repair; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Nuclear Proteins; Protein Binding; Protein Processing, Post-Translational; Transcription Factors; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7; Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 25962961
DOI: 10.18632/oncotarget.3922 -
Nature Methods Dec 2020A soccer striker and his ion channel rescue tools.
A soccer striker and his ion channel rescue tools.
Topics: Biophysics; Deubiquitinating Enzymes; History, 20th Century; History, 21st Century; Humans; Ion Channels; Ubiquitin
PubMed: 33208977
DOI: 10.1038/s41592-020-01012-3 -
Journal of Molecular Biology Nov 2017Ubiquitin and ubiquitin-modifying enzymes play critical roles in a wide variety of intracellular signaling pathways. Inflammatory signaling cascades downstream of TNF,... (Review)
Review
Ubiquitin and ubiquitin-modifying enzymes play critical roles in a wide variety of intracellular signaling pathways. Inflammatory signaling cascades downstream of TNF, TLR agonists, antigen receptor cross-linking, and cytokine receptors, all rely on ubiquitination events to direct subsequent immune responses. In the past several years, inflammasome activation and subsequent signal transduction have emerged as an excellent example of how ubiquitin signals control inflammatory responses. Inflammasomes are multiprotein signaling complexes that ultimately lead to caspase activation and release of the interleukin-1 (IL-1) family members, IL-1β and IL-18. Inflammasome activation is critical for the host's defense against pathogens, but dysregulation of inflammasomes may contribute to the pathogenesis of multiple diseases. Ultimately, understanding how various ubiquitin interacting proteins control inflammatory signaling cascades could provide new pathways for therapeutic intervention. Here we review specific ubiquitin-modifying enzymes and ubiquitination events that orchestrate inflammatory responses, with an emphasis on the NLRP3 inflammasome.
Topics: Animals; Deubiquitinating Enzymes; Humans; Inflammasomes; Ubiquitin; Ubiquitin-Protein Ligase Complexes
PubMed: 29031697
DOI: 10.1016/j.jmb.2017.10.001 -
Cancer Metastasis Reviews Dec 2017Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the... (Review)
Review
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
Topics: Animals; Deubiquitinating Enzymes; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 29134486
DOI: 10.1007/s10555-017-9697-6 -
Cells Feb 2023Parkinson's disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as α-synuclein-positive inclusions, termed Lewy bodies (LBs), which are a common pathological hallmark in PD. Mitophagy is a process that maintains cellular health by eliminating dysfunctional mitochondria, and it is triggered by ubiquitination of mitochondrial-associated proteins-e.g., through the PINK1/Parkin pathway-which results in engulfment by the autophagosome and degradation in lysosomes. Deubiquitinating enzymes (DUBs) can regulate this process at several levels by deubiquitinating mitochondrial substrates and other targets in the mitophagic pathway, such as Parkin. Moreover, DUBs can affect α-synuclein aggregation through regulation of degradative pathways, deubiquitination of α-synuclein itself, and/or via co-localization with α-synuclein in inclusions. DUBs with a known association to PD are described in this paper, along with their function. Of interest, DUBs could be useful as novel therapeutic targets against PD through regulation of PD-associated defects.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Ubiquitin-Protein Ligases; Ubiquitination; Deubiquitinating Enzymes
PubMed: 36831318
DOI: 10.3390/cells12040651 -
International Journal of Molecular... Jun 2020Ubiquitination and deubiquitination play a critical role in all aspects of cellular processes, and the enzymes involved are tightly regulated by multiple factors... (Review)
Review
Ubiquitination and deubiquitination play a critical role in all aspects of cellular processes, and the enzymes involved are tightly regulated by multiple factors including posttranslational modifications like most other proteins. Dysfunction or misregulation of these enzymes could have dramatic physiological consequences, sometimes leading to diseases. Therefore, it is important to have a clear understanding of these regulatory processes. Here, we have reviewed the posttranslational modifications of deubiquitinating enzymes and their consequences on the catalytic activity, stability, abundance, localization, and interaction with the partner proteins.
Topics: Catalysis; Deubiquitinating Enzymes; Humans; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Ubiquitin; Ubiquitination
PubMed: 32512887
DOI: 10.3390/ijms21114028