scholarly journals Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Marie-José Bijlmakers
Keyword(s):  
Drug Targets ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Efficacy And Safety ◽  
Cellular Processes ◽  
Therapeutic Drugs ◽  
Selective Targeting ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Novel Drug

The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

scholarly journals The ubiquitin proteasome system in synaptic and axonal degeneration

2004 ◽  
Vol 165 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Laura Korhonen ◽  
Dan Lindholm
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Targets ◽  
Axonal Degeneration ◽  
Fruit Fly ◽  
Ubiquitin Proteasome System ◽  
Synaptic Protein ◽  
Ubiquitin Proteasome ◽  
Novel Drug ◽  
Novel Drug Targets

The ubiquitin proteasome system (UPS) contributes to the pathophysiology of neurodegenerative diseases, and it is also a major determinant of synaptic protein degradation and activity. Recent studies in rodents and in the fruit fly Drosophila have shown that the activity of the UPS is involved in axonal degeneration. Increased knowledge of the UPS in synaptic and axonal reactions may provide novel drug targets for treatments of neuronal injuries and neurodegenerative disorders.

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.

scholarly journals Immunoproteasome Function in Normal and Malignant Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1577
Author(s):  
Nuria Tubío-Santamaría ◽  
Frédéric Ebstein ◽  
Florian H. Heidel ◽  
Elke Krüger
Keyword(s):  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Efficacy And Safety ◽  
Hematopoietic System ◽  
Oxidized Proteins ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Early Phases

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

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 Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3764
Author(s):  
Matthias Wirth ◽  
Markus Schick ◽  
Ulrich Keller ◽  
Jan Krönke
Keyword(s):  
Multiple Myeloma ◽  
Translational Regulation ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Organ Damage ◽  
Post Translational Modifications ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
New Treatments ◽  
Effective Drugs

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.

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 Regulation of Ubiquitin-Proteasome System–mediated Degradation by Cytosolic Stress

2007 ◽  
Vol 18 (11) ◽  
pp. 4279-4291 ◽  
Author(s):  
Sean M. Kelly ◽  
Judy K. VanSlyke ◽  
Linda S. Musil
Keyword(s):  
Heat Shock ◽  
Secretory Pathway ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Junction Protein ◽  
Ubiquitin Proteasome ◽  
Gap Junction Protein ◽  
Cystic Fibrosis Transmembrane

ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild-type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42°C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP-ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation.

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.

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