scholarly journals A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1929
Author(s):  
Eva M. Huber ◽  
Michael Groll
Keyword(s):  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cell Signalling ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Chemical Structures ◽  
Phase Ii Clinical Trials ◽  
Ubiquitin Proteasome ◽  
Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

Ubiquitin and control of transcription

2005 ◽  
Vol 41 ◽  
pp. 69-80 ◽  
Author(s):  
Sarath C. Dhananjayan ◽  
Ayesha Ismail ◽  
Zafar Nawaz
Keyword(s):  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Regulatory System ◽  
Ubiquitin Proteasome System ◽  
Activation Function ◽  
Regulation Of Transcription ◽  
Cellular Processes ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome ◽  
Transcription Complexes

Eukaryotic transcription is one of the most complex cellular processes and constitutes the first step in protein synthesis. Ubiquitination and subsequent degradation by the 26 S proteasome, on the other hand, represents the final chapter in the life of a protein. Intriguingly, ubiquitin and the ubiquitin– proteasome system play vital roles in the regulation of transcription. Ubiquitin has dual modus operandi: firstly, ubiquitin functions via the 26 S proteasome — it is tagged to components of the transcription machinery, marking them for degradation via the proteasome, which results in the proper exchange of complexes during transcription and the prompt removal of activators after each round of transcription; and secondly, ubiquitin can function independently of the proteasome — histone ubiquitination results in heterochromatin relaxation and assembly of transcription complexes on the promoter, and ubiquitination of transcription factors enhances their transcriptional-activation function. Although ubiquitin and the ubiquitin–proteasome system were initially perceived as a graveyard for proteins, recent advances in molecular biological techniques have redefined their role as a regulatory system that influences the fate of many cellular processes, such as apoptosis, transcription and cell cycle progression.

scholarly journals Tuning the proteasome to brighten the end of the journey

2016 ◽  
Vol 311 (5) ◽  
pp. C793-C804 ◽  
Author(s):  
Thibault Mayor ◽  
Michal Sharon ◽  
Michael H. Glickman
Keyword(s):  
Cell Cycle Progression ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cellular Proteins ◽  
Regulatory Mechanisms ◽  
Protein Homeostasis ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Age Related ◽  
Ubiquitin Proteasome

Degradation by the proteasome is the fate for a large portion of cellular proteins, and it plays a major role in maintaining protein homeostasis, as well as in regulating many cellular processes like cell cycle progression. A decrease in proteasome activity has been linked to aging and several age-related neurodegenerative pathologies and highlights the importance of the ubiquitin proteasome system regulation. While the proteasome has been traditionally viewed as a constitutive element of proteolysis, major studies have highlighted how different regulatory mechanisms can impact its activity. Importantly, alterations of proteasomal activity may have major impacts for its function and in therapeutics. On one hand, increasing proteasome activity could be beneficial to prevent the age-related downfall of protein homeostasis, whereas inhibiting or reducing its activity can prevent the proliferation of cancer cells.

scholarly journals Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential

2021 ◽  
Vol 15 ◽  
Author(s):  
Yu Yang ◽  
Xuan Zhou ◽  
Xinpeng Liu ◽  
Ruying Song ◽  
Yiming Gao ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Potential Therapeutic Target ◽  
Cellular Processes ◽  
Wide Range ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Accumulated evidence shows that FBXW7 is fundamental to neurological functions and especially implicated in neurodevelopment and the nosogenesis of neurodegeneration. In this review, we describe general features of FBXW7 gene and proteins, and mainly present recent findings that highlight the vital roles and molecular mechanisms of FBXW7 in neurodevelopment such as neurogenesis, myelination and cerebral vasculogenesis and in the pathogenesis of some typical neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Additionally, we also provide a prospect on focusing FBXW7 as a potential therapeutic target to rescue neurodevelopmental and neurodegenerative impairment.

scholarly journals Ubiquitin carboxyl-terminal hydrolases are required for period maintenance of the circadian clock at high temperature in Arabidopsis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryosuke Hayama ◽  
Peizhen Yang ◽  
Federico Valverde ◽  
Tsuyoshi Mizoguchi ◽  
Ikuyo Furutani-Hayama ◽  
...  
Keyword(s):  
Circadian Clock ◽  
High Temperatures ◽  
Elevated Temperatures ◽  
Control Period ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
Cellular Processes ◽  
Control Functions ◽  
Ubiquitin Proteasome ◽  
Carboxyl Terminal

AbstractProtein ubiquitylation participates in a number of essential cellular processes including signal transduction and transcription, often by initiating the degradation of specific substrates through the 26S proteasome. Within the ubiquitin-proteasome system, deubiquitylating enzymes (DUBs) not only help generate and maintain the supply of free ubiquitin monomers, they also directly control functions and activities of specific target proteins by modulating the pool of ubiquitylated species. Ubiquitin carboxyl-terminal hydrolases (UCHs) belong to an enzymatic subclass of DUBs, and are represented by three members in Arabidopsis, UCH1, UCH2 and UCH3. UCH1 and UCH2 influence auxin-dependent developmental pathways in Arabidopsis through their deubiquitylation activities, whereas biological and enzymatic functions of UCH3 remain unclear. Here, we demonstrate that Arabidopsis UCH3 acts to maintain the period of the circadian clock at high temperatures redundantly with UCH1 and UCH2. Whereas single uch1, uch2 and uch3 mutants have weak circadian phenotypes, the triple uch mutant displays a drastic lengthening of period at high temperatures that is more extreme than the uch1 uch2 double mutant. UCH3 also possesses a broad deubiquitylation activity against a range of substrates that link ubiquitin via peptide and isopeptide linkages. While the protein target(s) of UCH1-3 are not yet known, we propose that these DUBs act on one or more factors that control period length of the circadian clock through removal of their bound ubiquitin moieties, thus ensuring that the clock oscillates with a proper period even at elevated temperatures.

scholarly journals TRIM Proteins and Their Roles in the Influenza Virus Life Cycle

2020 ◽  
Vol 8 (9) ◽  
pp. 1424
Author(s):  
Hye-Ra Lee ◽  
Myoung Kyu Lee ◽  
Chan Woo Kim ◽  
Meehyein Kim
Keyword(s):  
Influenza Virus ◽  
Signaling Pathways ◽  
Viral Infections ◽  
Influenza Virus Infection ◽  
Ubiquitin Proteasome System ◽  
Viral Propagation ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Immune Sensing ◽  
Trim Proteins

The ubiquitin-proteasome system (UPS) has been recognized for regulating fundamental cellular processes, followed by induction of proteasomal degradation of target proteins, and triggers multiple signaling pathways that are crucial for numerous aspects of cellular physiology. Especially tripartite motif (TRIM) proteins, well-known E3 ubiquitin ligases, emerge as having critical roles in several antiviral signaling pathways against varying viral infections. Here we highlight recent advances in the study of antiviral roles of TRIM proteins toward influenza virus infection in terms of the modulation of pathogen recognition receptor (PRR)-mediated innate immune sensing, direct obstruction of influenza viral propagation, and participation in virus-induced autophagy.

scholarly journals The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

2007 ◽  
Vol 177 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Megan L. Landsverk ◽  
Shumin Li ◽  
Alex H. Hutagalung ◽  
Ayaz Najafov ◽  
Thorsten Hoppe ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Proteasome Inhibition ◽  
Thick Filament ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Myosin Motors ◽  
And Function ◽  
Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

scholarly journals Efficient APC/C substrate degradation in cells undergoing mitotic exit depends on K11 ubiquitin linkages

2015 ◽  
Vol 26 (24) ◽  
pp. 4325-4332 ◽  
Author(s):  
Mingwei Min ◽  
Tycho E. T. Mevissen ◽  
Maria De Luca ◽  
David Komander ◽  
Catherine Lindon
Keyword(s):  
Cell Cycle Progression ◽  
Degradation Kinetics ◽  
Ubiquitin Proteasome System ◽  
Mitotic Exit ◽  
Anaphase Promoting Complex ◽  
Polyubiquitin Chains ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome ◽  
In Cells

The ubiquitin proteasome system (UPS) directs programmed destruction of key cellular regulators via posttranslational modification of its targets with polyubiquitin chains. These commonly contain Lys-48 (K48)–directed ubiquitin linkages, but chains containing atypical Lys-11 (K11) linkages also target substrates to the proteasome—for example, to regulate cell cycle progression. The ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C) controls mitotic exit. In higher eukaryotes, the APC/C works with the E2 enzyme UBE2S to assemble K11 linkages in cells released from mitotic arrest, and these are proposed to constitute an improved proteolytic signal during exit from mitosis. We tested this idea by correlating quantitative measures of in vivo K11-specific ubiquitination of individual substrates, including Aurora kinases, with their degradation kinetics tracked at the single-cell level. All anaphase substrates tested by this methodology are stabilized by depletion of K11 linkages via UBE2S knockdown, even if the same substrates are significantly modified with K48-linked polyubiquitin. Specific examination of substrates depending on the APC/C coactivator Cdh1 for their degradation revealed Cdh1-dependent enrichment of K11 chains on these substrates, whereas other ubiquitin linkages on the same substrates added during mitotic exit were Cdh1-independent. Therefore we show that K11 linkages provide the APC/C with a means to regulate the rate of substrate degradation in a coactivator-specified manner.

scholarly journals Designing HDAC-PROTACs: lessons learned so far

2021 ◽  
Author(s):  
Fabian Fischer ◽  
Leandro A Alves Avelar ◽  
Laoise Murray ◽  
Thomas Kurz
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Hormone Receptors ◽  
Ubiquitin Proteasome System ◽  
Research Field ◽  
Lessons Learned ◽  
Binding Motifs ◽  
Phase Ii Clinical Trials ◽  
Traditional Drug ◽  
Ubiquitin Proteasome ◽  
Key Steps

Proteolysis-targeting chimeras (PROTACs) are a powerful tool to hijack the endogenous ubiquitin-proteasome system (UPS) and to degrade the intracellular proteins of therapeutic importance. Recently, two heterobifunctional degraders targeting hormone receptors headed into Phase II clinical trials. Compared to traditional drug design and common modes of action, the PROTAC approach offers new opportunities for the drug research field. Histone deacetylase inhibitors (HDACi) are well-established drugs for the treatment of hematological malignancies. The integration of HDAC binding motifs in PROTACs explores the possibility of targeted, chemical HDAC degradation. This review provides an overview and a perspective about the key steps in the structure development of HDAC–PROTACs. In particular, the influence of the three canonical PROTAC elements on HDAC–PROTAC efficacy and selectivity are discussed, the HDACi, the linker and the E3 ligase ligand.

Targeting of host-cell ubiquitin pathways by viruses

2005 ◽  
Vol 41 ◽  
pp. 139-156 ◽  
Author(s):  
Julia Shackelford ◽  
Joseph S. Pagano
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Cell Signalling ◽  
Ubiquitin Proteasome System ◽  
Life Cycles ◽  
Therapeutic Interventions ◽  
Signalling Pathways ◽  
Cellular Functions ◽  
Ubiquitin Proteasome ◽  
Do So

The ability of viruses to co-opt cell signalling pathways has, over millions of years of co-evolution, come to pervade nearly every facet of cellular functions. Recognition of the extent to which the ubiquitin–proteasome system can be directed or subverted by viruses is relatively recent. Viral products interact with, and adjust, the ubiquitin–proteasome machinery precisely and at many levels, and they do so at distinct stages of viral life-cycles. The implications for both cells and viruses are fundamental, and understanding viral strategies in this context opens up fascinating new areas for research that span from basic cell biology to therapeutic interventions against both viruses and malignancies.

Fluorescent reporters for the ubiquitin–proteasome system

2005 ◽  
Vol 41 ◽  
pp. 113-128 ◽  
Author(s):  
Florian A. Salomons ◽  
Lisette G.G.C. Verhoef ◽  
Nico P. Dantuma
Keyword(s):  
High Efficiency ◽  
Fluorescent Protein ◽  
Fluorescent Proteins ◽  
Ubiquitin Proteasome System ◽  
Fluorescent Reporters ◽  
Cellular Processes ◽  
The Status ◽  
Ubiquitin Proteasome ◽  
Green Fluorescent ◽  
Specific Degradation

Regulated turnover of proteins in the cytosol and nucleus of eukaryotic cells is primarily performed by the ubiquitin–proteasome system (UPS). The UPS is involved in many essential cellular processes. Alterations in this proteolytic system are associated with a variety of human pathologies, such as neurodegenerative diseases, cancer, immunological disorders and inflammation. The precise role of the UPS in the pathophysiology of these diseases, however, remains poorly understood. Detection of UPS aberrations has been a major challenge because of the complexity of the system. Most studies focus on various aspects of the UPS, such as substrate recognition, ubiquitination, deubiquitination or proteasome activity, and do not provide a complete picture of the UPS as an integral system. To monitor the efficacy of the UPS, a number of reporter substrates have been developed based on fluorescent proteins, such as the green fluorescent protein and its spectral variants. These fluorescent UPS reporters contain specific degradation signals that target them with high efficiency and accuracy for proteasomal degradation. Several studies have shown that these reporters can probe the functionality of the UPS in cellular and animal models and provide us with important information on the status of the UPS under various conditions. Moreover, these reporters can aid the identification and development of novel anti-cancer and anti-inflammatory drugs based on UPS inhibition.

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