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Biomolecules Jul 2021The gut epithelial barrier provides the first line of defense protecting the internal milieu from the environment. To circumvent the exposure to constant challenges such... (Review)
Review
The gut epithelial barrier provides the first line of defense protecting the internal milieu from the environment. To circumvent the exposure to constant challenges such as pathogenic infections and commensal bacteria, epithelial and immune cells at the gut barrier require rapid and efficient means to dynamically sense and respond to stimuli. Numerous studies have highlighted the importance of proteolysis in maintaining homeostasis and adapting to the dynamic changes of the conditions in the gut environment. Primarily, proteolytic activities that are involved in immune regulation and inflammation have been examined in the context of the lysosome and inflammasome activation. Yet, the key to cellular and tissue proteostasis is the ubiquitin-proteasome system, which tightly regulates fundamental aspects of inflammatory signaling and protein quality control to provide rapid responses and protect from the accumulation of proteotoxic damage. In this review, we discuss proteasome-dependent regulation of the gut and highlight the pathophysiological consequences of the disarray of proteasomal control in the gut, in the context of aberrant inflammatory disorders and tumorigenesis.
Topics: Animals; Enzyme Activation; Humans; Inflammation; Intestinal Mucosa; Lysosomes; Proteasome Endopeptidase Complex; Proteolysis; Signal Transduction
PubMed: 34356615
DOI: 10.3390/biom11070989 -
Journal of Clinical Immunology Apr 2024The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions,... (Review)
Review
The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions, including immune responses. The proteasome complex is ubiquitously expressed and is responsible for degradation of short-lived structurally abnormal, misfolded and not-needed proteins that are targeted for degradation via ubiquitin conjugation. Over the last 14 years, an increasing number of human diseases have been linked to pathogenic variants in proteasome subunits and UPS regulators. Defects of the proteasome complex or its chaperons - which have a regulatory role in the assembly of the proteasome - disrupt protein clearance and cellular homeostasis, leading to immune dysregulation, severe inflammation, and neurodevelopmental disorders in humans. Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited. In this review, we summarize the current known genetic causes of proteasomal disease, and discuss the molecular pathogenesis of these conditions based on the function and cellular expression of mutated proteins in the proteasome complex.
Topics: Humans; Proteasome Endopeptidase Complex; Syndrome; Ubiquitin
PubMed: 38578475
DOI: 10.1007/s10875-024-01692-y -
Journal of Molecular Biology Nov 2017Three deubiquitinating enzymes-Rpn11, Usp14, and Uch37-are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from... (Review)
Review
Three deubiquitinating enzymes-Rpn11, Usp14, and Uch37-are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel's entry port, where they can impede further translocation. Rpn11, situated over the port, can remove these chains without compromising degradation because substrates must be irreversibly committed to degradation before Rpn11 acts. This coupling between deubiquitination and substrate degradation is ensured by the Ins-1 loop of Rpn11, which controls ubiquitin access to its catalytic site. In contrast to Rpn11, Usp14 and Uch37 can rescue substrates from degradation by promoting substrate dissociation from the proteasome prior to the commitment step. Uch37 is unique in being a component of both the proteasome and a second multisubunit assembly, the INO80 complex. However, only recruitment into the proteasome activates Uch37. Recruitment to the proteasome likewise activates Usp14. However, the influence of Usp14 on the proteasome depends on the substrate, due to its marked preference for proteins that carry multiple ubiquitin chains. Usp14 exerts complex control over the proteasome, suppressing proteasome activity even when inactive in deubiquitination. A major challenge for the field will be to elucidate the specificities of Rpn11, Usp14, and Uch37 in greater depth, employing not only model in vitro substrates but also their endogenous targets.
Topics: Deubiquitinating Enzymes; Eukaryotic Cells; Hydrolysis; Proteasome Endopeptidase Complex; Protein Transport; Proteolysis
PubMed: 28988953
DOI: 10.1016/j.jmb.2017.09.015 -
Archives of Biochemistry and Biophysics Feb 2016The 20S proteasome is a multicatalytic proteinase catalysing the degradation of the majority of intracellular proteins. Thereby it is involved in almost all basic... (Review)
Review
The 20S proteasome is a multicatalytic proteinase catalysing the degradation of the majority of intracellular proteins. Thereby it is involved in almost all basic cellular processes, which is facilitated by its association with various regulator complexes so that it appears in different disguises like 26S proteasome, hybrid-proteasome and others. The 20S proteasome has a cylindrical structure built up by four stacked rings composed of α- and β-subunits. Since the three active site-containing β-subunits can all or in part be replaced by immuno-subunits, three main subpopulations exist, namely standard-, immuno- and intermediate-proteasomes. Due to posttranslational modifications or/and genetic variations all α- and β-subunits occur in multiple iso- or proteoforms. This leads to the fact that each of the three subpopulations is composed of a variety of 20S proteasome subtypes. This review summarizes the knowledge of proteasome subtypes in mammalian cells and tissues and their possible biological and medical relevancy.
Topics: Animals; Genetic Variation; Humans; Proteasome Endopeptidase Complex
PubMed: 26724758
DOI: 10.1016/j.abb.2015.12.012 -
Current Opinion in Pharmacology Dec 2022The ubiquitin proteasome system (UPS) is a proteolytic machinery for the degradation of protein substrates that are post-translationally conjugated with ubiquitin... (Review)
Review
The ubiquitin proteasome system (UPS) is a proteolytic machinery for the degradation of protein substrates that are post-translationally conjugated with ubiquitin polymers through the enzymatic action of ubiquitin ligases, in a process termed ubiquitylation. Ubiquitylation of substrates precedes their proteolysis via proteasomes, a hierarchical feature of UPS. E3-ubiquitin ligases recruit protein substrates providing specificity for ubiquitylation. Innate and adaptive immune system networks are regulated by ubiquitylation and substrate degradation via E3-ligases/UPS. Deregulation of E3-ligases/UPS components in immune cells is involved in the development of lymphomas, neurodevelopmental abnormalities, and cancers. Targeting E3-ligases for therapeutic intervention provides opportunities to mitigate the unintended broad effects of 26S proteasome inhibition. Recently, bifunctional moieties such as PROTACs and molecular glues have been developed to re-purpose E3-ligases for targeted degradation of unwanted aberrant proteins, with a potential for clinical use. Here, we summarize the involvement of E3-ligases/UPS components in immune-related diseases with perspectives.
Topics: Humans; Ubiquitin; Proteasome Endopeptidase Complex; Ubiquitin-Protein Ligases; Proteolysis; Proteins
PubMed: 36288660
DOI: 10.1016/j.coph.2022.102310 -
Methods in Molecular Biology (Clifton,... 2021We use an in vitro degradation assay with a model substrate to assess proteasomal unfolding ability. Our substrate has an unstructured region that is the site of...
We use an in vitro degradation assay with a model substrate to assess proteasomal unfolding ability. Our substrate has an unstructured region that is the site of ubiquitination, followed by an easy-to-unfold domain and a difficult-to-unfold domain. Degradation proceeds through the unstructured and easy-to-unfold domains, but the difficult-to-unfold domain can be degraded completely or, if the proteasome stalls, can be released as a partially degraded fragment. The ratio between these two possible outcomes allows us to quantify the unfolding ability and determine how processively the proteasome degrades its substrates.
Topics: Cytoplasm; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination
PubMed: 34432247
DOI: 10.1007/978-1-0716-1665-9_12 -
Antioxidants & Redox Signaling Dec 2014The proteasome is the degradation machine of the ubiquitin-proteasome system, which is critical in controlling many essential biological processes. Aberrant regulation... (Review)
Review
SIGNIFICANCE
The proteasome is the degradation machine of the ubiquitin-proteasome system, which is critical in controlling many essential biological processes. Aberrant regulation of proteasome-dependent protein degradation can lead to various human diseases, and general proteasome inhibitors have shown efficacy for cancer treatments. Though clinically effective, current proteasome inhibitors have detrimental side effects and, thus, better therapeutic strategies targeting proteasomes are needed. Therefore, a comprehensive characterization of proteasome complexes will provide the molecular details that are essential for developing new and improved drugs.
RECENT ADVANCES
New mass spectrometry (MS)-based proteomics approaches have been developed to study protein interaction networks and structural topologies of proteasome complexes. The results have helped define the dynamic proteomes of proteasome complexes, thus providing new insights into the mechanisms underlying proteasome function and regulation.
CRITICAL ISSUES
The proteasome exists as heterogeneous populations in tissues/cells, and its proteome is highly dynamic and complex. In addition, proteasome complexes are regulated by various mechanisms under different physiological conditions. Consequently, complete proteomic profiling of proteasome complexes remains a major challenge for the field.
FUTURE DIRECTIONS
We expect that proteomic methodologies enabling full characterization of proteasome complexes will continue to evolve. Further advances in MS instrumentation and protein separation techniques will be needed to facilitate the detailed proteomic analysis of low-abundance components and subpopulations of proteasome complexes. The results will help us understand proteasome biology as well as provide new therapeutic targets for disease diagnostics and treatment.
Topics: Mass Spectrometry; Proteasome Endopeptidase Complex; Proteomics
PubMed: 24423446
DOI: 10.1089/ars.2013.5815 -
Biochemistry. Biokhimiia Jan 2019In the middle of the 20th century, it was postulated that degradation of intracellular proteins is a stochastic process. More than fifty years of intense studies have... (Review)
Review
In the middle of the 20th century, it was postulated that degradation of intracellular proteins is a stochastic process. More than fifty years of intense studies have finally proven that protein degradation is a very complex and tightly regulated in time and space process that plays an incredibly important role in the vast majority of metabolic pathways. Degradation of more than a half of intracellular proteins is controlled by a hierarchically aligned and evolutionarily perfect system consisting of many components, the main ones being ubiquitin ligases and proteasomes, together referred to as the ubiquitin-proteasome system (UPS). The UPS includes more than 1000 individual components, and most of them are critical for the cell functioning and survival. In addition to the well-known signaling functions of ubiquitination, such as modification of substrates for proteasomal degradation and DNA repair, polyubiquitin (polyUb) chains are involved in other important cellular processes, e.g., cell cycle regulation, immunity, protein degradation in mitochondria, and even mRNA stability. This incredible variety of ubiquitination functions is related to the ubiquitin ability to form branching chains through the ε-amino group of any of seven lysine residues in its sequence. Deubiquitination is accomplished by proteins of the deubiquitinating enzyme family. The second main component of the UPS is proteasome, a multisubunit proteinase complex that, in addition to the degradation of functionally exhausted and damaged proteins, regulates many important cellular processes through controlled degradation of substrates, for example, transcription factors and cyclins. In addition to the ubiquitin-dependent-mediated degradation, there is also ubiquitin-independent degradation, when the proteolytic signal is either an intrinsic protein sequence or shuttle molecule. Protein hydrolysis is a critically important cellular function; therefore, any abnormalities in this process lead to systemic impairments further transforming into serious diseases, such as diabetes, malignant transformation, and neurodegenerative disorders (multiple sclerosis, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease and Huntington's disease). In this review, we discuss the mechanisms that orchestrate all components of the UPS, as well as the plurality of the fine-tuning pathways of proteasomal degradation.
Topics: Humans; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteolysis; Signal Transduction; Ubiquitination; Ubiquitins
PubMed: 31213201
DOI: 10.1134/S0006297919140104 -
Mini Reviews in Medicinal Chemistry 2021Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC)... (Review)
Review
Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC) technology involves the degradation of target protein against the inhibition by small drug molecules. The PROTACs with high potency and activity have been frequently reported; however, no PROTAC acting against cancer has reached the clinical trials. The concept of PROTACs involves the reduction in the disease-causing protein by its degradation through the ubiquitin-proteasomal enzyme system. This concept has attracted a lot of attention from both industry and academia due to its potential in drug discovery (in the form of PROTACs), which can conquer the resistance associated with current treatments of cancer. Thus, it is the need of the hour to identify and synthesize more PROTACs for a viable treatment of cancer. This article reviews the design, activity and effects produced in cancer by some recently developed PROTACs.
Topics: Drug Resistance, Neoplasm; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 33634757
DOI: 10.2174/1389557521666210226150740 -
Biomolecules Mar 2020This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of... (Review)
Review
This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs-in particular, the expression of immune proteasomes-is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.
Topics: Animals; Cysteine Endopeptidases; Gene Expression Regulation; Humans; Proteasome Endopeptidase Complex; Receptors, Estrogen; Ubiquitin; Ubiquitin-Protein Ligase Complexes
PubMed: 32224970
DOI: 10.3390/biom10040500