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Nature Reviews. Drug Discovery Jan 2018More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase... (Review)
Review
More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.
Topics: Deubiquitinating Enzymes; Drug Discovery; Drug Industry; Drugs, Investigational; Humans; Molecular Targeted Therapy; Neoplasms; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 28959952
DOI: 10.1038/nrd.2017.152 -
Molecular Cell Jan 2022Deubiquitinases (DUBs) are specialized proteases that remove ubiquitin from substrates or cleave within ubiquitin chains to regulate ubiquitylation and therefore play... (Review)
Review
Deubiquitinases (DUBs) are specialized proteases that remove ubiquitin from substrates or cleave within ubiquitin chains to regulate ubiquitylation and therefore play important roles in eukaryotic biology. Dysregulation of DUBs is implicated in several human diseases, highlighting the importance of DUB function. In addition, many pathogenic bacteria and viruses encode and deploy DUBs to manipulate host immune responses and establish infectious diseases in humans and animals. Hence, therapeutic targeting of DUBs is an increasingly explored area that requires an in-depth mechanistic understanding of human and pathogenic DUBs. In this review, we summarize the multiple layers of regulation that control autoinhibition, activation, and substrate specificity of DUBs. We discuss different strategies to inhibit DUBs and the progress in developing selective small-molecule DUB inhibitors. Finally, we propose a classification system of DUB inhibitors based on their mode of action.
Topics: COVID-19; Deubiquitinating Enzymes; Enzyme Inhibitors; Humans; SARS-CoV-2; Ubiquitination; COVID-19 Drug Treatment
PubMed: 34813758
DOI: 10.1016/j.molcel.2021.10.027 -
Biochimica Et Biophysica Acta. Reviews... May 2022The mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation,... (Review)
Review
The mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation, and stress responses. This pathway converts external stimuli to cellular responses via three major kinases: mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase (MAPKK), and mitogen-activated protein kinase kinase kinase (MAPKKK). Ubiquitination is a post-translational modification of proteins with ubiquitin, which results in the formation of mono- or poly-ubiquitin chains of substrate proteins. Conversely, removal of the ubiquitin by deubiquitinating enzymes (DUBs) is known as deubiquitination. This review summarizes mechanisms of the MAPK signaling pathways (ERK1/2, ERK5, p38, and JNK1/2/3 signaling pathway) in cancers, and of E3 ligases and DUBs that target the MAPK signaling components such as Raf, MEK1/2, ERK1/2, MEKK2/3, MEKK1-4, TAK1, DLK1, MLK1-4, ASK1/2, and MKK3-7.
Topics: Deubiquitinating Enzymes; Enzyme Activation; Humans; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Signal Transduction; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 35589008
DOI: 10.1016/j.bbcan.2022.188736 -
Annual Review of Biochemistry Jun 2018As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic... (Review)
Review
As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.
Topics: ATPases Associated with Diverse Cellular Activities; Deubiquitinating Enzymes; Humans; Models, Biological; Models, Molecular; Molecular Motor Proteins; Proteasome Endopeptidase Complex; Protein Conformation; Saccharomyces cerevisiae Proteins; Substrate Specificity; Ubiquitin
PubMed: 29652515
DOI: 10.1146/annurev-biochem-062917-011931 -
The Journal of Biological Chemistry Sep 2021Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity,... (Review)
Review
Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein-protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.
Topics: Animals; Deubiquitinating Enzymes; Endopeptidases; Homeostasis; Humans; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Reactive Oxygen Species; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 34391779
DOI: 10.1016/j.jbc.2021.101077 -
DNA Repair Apr 2019Turnover of cellular proteins is regulated by Ubiquitin Proteasome System (UPS). Components of this pathway, including the proteasome, ubiquitinating enzymes and... (Review)
Review
Turnover of cellular proteins is regulated by Ubiquitin Proteasome System (UPS). Components of this pathway, including the proteasome, ubiquitinating enzymes and deubiquitinating enzymes, are highly specialized and tightly regulated. In this mini-review we focus on the de-ubiquitinating enzyme USP7, and summarize latest advances in understanding its structure, substrate specificity and relevance to human cancers. There is increasing interest in UPS components as targets for cancer therapy and here we also overview the recent progress in the development of small molecule inhibitors that target USP7.
Topics: Animals; Enzyme Inhibitors; Humans; Substrate Specificity; Ubiquitin-Specific Peptidase 7
PubMed: 30807924
DOI: 10.1016/j.dnarep.2019.02.005 -
Annual Review of Biochemistry Jun 2017Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners.... (Review)
Review
Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners. Simple monoubiquitination events coexist with more complex forms of polyubiquitination, the latter featuring many different chain architectures. Ubiquitin can be subjected to further posttranslational modifications (e.g., phosphorylation and acetylation) and can also be part of mixed polymers with ubiquitin-like modifiers such as SUMO (small ubiquitin-related modifier) or NEDD8 (neural precursor cell expressed, developmentally downregulated 8). Together, cellular ubiquitination events form a sophisticated and versatile ubiquitin code. Deubiquitinases (DUBs) reverse ubiquitin signals with equally high sophistication. In this review, we conceptualize the many layers of specificity that DUBs encompass to control the ubiquitin code and discuss examples in which DUB specificity has been understood at the molecular level. We further discuss the many mechanisms of DUB regulation with a focus on those that modulate catalytic activity. Our review provides a framework to tackle lingering questions in DUB biology.
Topics: Acetylation; Allosteric Regulation; Deubiquitinating Enzymes; Eukaryotic Cells; Humans; Models, Molecular; NEDD8 Protein; Phosphorylation; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Proteolysis; Substrate Specificity; Sumoylation; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitins
PubMed: 28498721
DOI: 10.1146/annurev-biochem-061516-044916 -
Nature Reviews. Cancer Dec 2023Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and,... (Review)
Review
Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.
Topics: Humans; Ubiquitination; Ubiquitin; Neoplasms; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes
PubMed: 37935888
DOI: 10.1038/s41568-023-00633-y -
Nature Communications May 2022The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely...
The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely unknown. Here, we compare the contributions of the proteasome and DUBs on the global ubiquitinome, using UbiSite technology, inhibitors and mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates and sites preferentially regulated by DUBs or by the proteasome, highlighting the role of DUBs in degradation-independent ubiquitination. DUBs regulate substrates via at least 40,000 unique sites. Regulated networks of ubiquitin substrates are involved in autophagy, apoptosis, genome integrity, telomere integrity, cell cycle progression, mitochondrial function, vesicle transport, signal transduction, transcription, pre-mRNA splicing and many other cellular processes. Moreover, we show that ubiquitin conjugated to SUMO2/3 forms a strong proteasomal degradation signal. Interestingly, PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity. Our study uncovers key regulatory roles of DUBs and provides a resource of endogenous ubiquitination sites to aid the analysis of substrate specific ubiquitin signalling.
Topics: Cell Division; Deubiquitinating Enzymes; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitination
PubMed: 35585066
DOI: 10.1038/s41467-022-30376-7 -
Journal of Medicinal Chemistry Mar 2020Deubiquitinating enzymes, or DUBs, comprise a family of proteases that regulate ubiquitination dynamics. Since their discovery, genetic and functional studies have... (Review)
Review
Deubiquitinating enzymes, or DUBs, comprise a family of proteases that regulate ubiquitination dynamics. Since their discovery, genetic and functional studies have nominated DUBs as a promising class for drug discovery across diverse therapeutic areas. Consequent probe and drug discovery efforts over the past 15 years have resulted in over 50 reported inhibitors and advances in DUB structural studies, assay formats, and chemical biology tools. Accumulating knowledge from these studies has enabled several important recent breakthroughs. In this review, we highlight recent successes in solving DUB-ligand co-structures and the development of rigorously characterized potent and selective inhibitors. We posit that these advances in pharmacological targeting of DUBs establish the enzyme family as targetable and provide a framework for other DUBs programs. Accordingly, we envision increasingly rapid progress in the development of potent and selective inhibitors for a wide range of DUBs and advancement of DUB-targeting drugs to the clinic.
Topics: Animals; Deubiquitinating Enzymes; Drug Development; Drug Discovery; Enzyme Inhibitors; Humans; Models, Molecular; Small Molecule Libraries; Ubiquitination
PubMed: 31682427
DOI: 10.1021/acs.jmedchem.9b01138