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 Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3431
Author(s):  
Levente Kollár ◽  
Martina Gobec ◽  
Matic Proj ◽  
Lara Smrdel ◽  
Damijan Knez ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Single Digit ◽  
Ic50 Values ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome

Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

scholarly journals The proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugates

2016 ◽  
Vol 212 (7) ◽  
pp. 789-801 ◽  
Author(s):  
Maria J. Pinto ◽  
Pedro L. Alves ◽  
Luís Martins ◽  
Joana R. Pedro ◽  
Hyun R. Ryu ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Presynaptic Terminal ◽  
Ubiquitinated Proteins ◽  
Presynaptic Differentiation ◽  
Intrinsic Mechanism ◽  
Ubiquitin Proteasome ◽  
Presynaptic Assembly ◽  
Local Modulation

Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin–proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses.

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 Strategies for the identification of ubiquitin ligase inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 132-136 ◽  
Author(s):  
Seth J. Goldenberg ◽  
Jeffrey G. Marblestone ◽  
Michael R. Mattern ◽  
Benjamin Nicholson
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
Therapeutic Strategy ◽  
Ubiquitin Proteasome System ◽  
Advantages And Disadvantages ◽  
Wide Range ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Effective Therapeutic Strategy ◽  
Protein Ligases

Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; however, toxicity with this target remains high. E3s (Ub–protein ligases) represent an alternative attractive therapeutic target in the UPS. In this paper, we will discuss current platforms that report on E3 ligase activity and can detect E3 inhibitors, and underline the advantages and disadvantages of each approach.

scholarly journals A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome

2008 ◽  
Vol 295 (6) ◽  
pp. H2541-H2550 ◽  
Author(s):  
Jinbao Liu ◽  
Hanqiao Zheng ◽  
Mingxin Tang ◽  
Youn-Chul Ryu ◽  
Xuejun Wang
Keyword(s):  
Critical Role ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Underlying Mechanism ◽  
3T3 Cells ◽  
New Findings ◽  
Relevant Dose ◽  
Ubiquitin Proteasome ◽  
Endogenous Substrates

The ubiquitin proteasome system (UPS) degrades abnormal proteins and most unneeded normal proteins, thereby playing a critical role in protein homeostasis in the cell. Proteasome inhibition is effective in treating certain forms of cancer, while UPS dysfunction is increasingly implicated in the pathogenesis of many severe and yet common diseases. It has been previously shown that doxorubicin (Dox) enhances the degradation of a UPS surrogate substrate in mouse hearts. To address the underlying mechanism, in the present study, we report that 1) Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes the proteasome inhibitor-induced accumulation of endogenous substrates (e.g., β-catenin and c-Jun) of the UPS in cultured NIH 3T3 cells and cardiomyocytes; 2) Dox facilitates the in vitro degradation of GFPu and c-Jun by the reconstituted UPS via the enhancement of proteasomal function; 3) Dox at a therapeutically relevant dose directly stimulates the peptidase activities of purified 20S proteasomes; and 4) Dox increases, whereas proteasome inhibition decreases, E3 ligase COOH-terminus of heat shock protein cognate 70 in 3T3 cells via a posttranscriptional mechanism. These new findings suggest that Dox activates the UPS by acting directly on both the ubiquitination apparatus and proteasome.

scholarly journals The Aspartyl Protease Ddi1 Is Essential for Erythrocyte Invasion by the Malaria Parasite

2021 ◽  
Author(s):  
Sophie Ridewood ◽  
Barbara Dirac-Svejstrup ◽  
Steven A Howell ◽  
Anne Weston ◽  
Christine Lehmann ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Blood Stream ◽  
Parasite Life Cycle ◽  
Erythrocyte Invasion ◽  
Multiple Components ◽  
Ubiquitin Proteasome ◽  
Inducible Protein

Malaria pathology is caused by the exponential replication of Plasmodium parasites in the blood stream. The bottleneck of the parasite life cycle is the invasion of erythrocytes immediately after parasites egress from infected red blood cells. DNA damage-inducible protein 1 (Ddi1) is a conserved eukaryotic proteasome shuttle protein containing an internal retroviral-like protease domain. Using conditional genetics, we now show that the proteolytic activity of the P. falciparum homologue, PfDdi1, is critically required for invasion of red blood cells. Furthermore, PfDdi1 disruption results in the accumulation of highly polyubiquitinated proteins that can be processed by purified PfDdi1 or distant eukaryotic homologues. We also show that PfDdi1 interacts with multiple components of the ubiquitin-proteasome system and that parasites lacking PfDdi1 are more sensitive to proteasome inhibition. Overall, this study establishes PfDdi1 as a key component of the eukaryotic ubiquitin-proteasome system and as a promising antimalarial target.

scholarly journals A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Liam Baird ◽  
Tadayuki Tsujita ◽  
Eri H. Kobayashi ◽  
Ryo Funayama ◽  
Takeshi Nagashima ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Conditional Knockout ◽  
Protein Homeostasis ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Inducible Systems

ABSTRACT Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

Targeting the Ubiquitin-proteasome System for the Treatment of Multiple Myeloma and Other Human Diseases

2010 ◽  
Vol 2 ◽  
pp. CMT.S2889
Author(s):  
Klaus Podar ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Human Diseases ◽  
Cellular Functions ◽  
Adverse Side Effects ◽  
Ubiquitin Proteasome ◽  
Novel Approaches

The ubiquitin-proteasome-degradation system plays a key role in multiple cellular functions. Its deregulation is associated with the initiation and progression of human diseases including not only solid and hematologic malignancies but also neurologic and autoimmune disorders. This article discusses several novel mechanistic aspects of the ubiquitin-proteasome system. Moreover, it focuses on the development, mechanisms of action, and clinical experience with Bortezomib, the first in-class-proteasome inhibitor to enter the clinics. Finally, it summarizes novel approaches to specifically target distinct components within the highly complex and dynamic ubiquitin-proteasome machinery to ultimately further increase drug activity, as well as reduce drug resistance and adverse side effects.

scholarly journals Molecular Chaperones and Proteolytic Machineries Regulate Protein Homeostasis in Aging Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1308 ◽  
Author(s):  
Boris Margulis ◽  
Anna Tsimokha ◽  
Svetlana Zubova ◽  
Irina Guzhova
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Molecular Chaperones ◽  
Ubiquitin Proteasome System ◽  
Life Cycles ◽  
Protein Homeostasis ◽  
Ubiquitin Proteasome ◽  
Correct Function ◽  
Regulate Protein

Throughout their life cycles, cells are subject to a variety of stresses that lead to a compromise between cell death and survival. Survival is partially provided by the cell proteostasis network, which consists of molecular chaperones, a ubiquitin-proteasome system of degradation and autophagy. The cooperation of these systems impacts the correct function of protein synthesis/modification/transport machinery starting from the adaption of nascent polypeptides to cellular overcrowding until the utilization of damaged or needless proteins. Eventually, aging cells, in parallel to the accumulation of flawed proteins, gradually lose their proteostasis mechanisms, and this loss leads to the degeneration of large cellular masses and to number of age-associated pathologies and ultimately death. In this review, we describe the function of proteostasis mechanisms with an emphasis on the possible associations between them.

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