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The Immunoproteasome in Health and Disease
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The Immunoproteasome in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 46412

Special Issue Editors

Prof. Dr. Marcus Groettrup

E-Mail Website
Guest Editor
Division of Immunology, Department of Biology, Universität Konstanz, D-78457 Konstanz, Germany
Interests: the immunoproteasome in antigen processing, leukocyte proteostasis, and T cell regulation; the conjugation, structure, and function of the ubiquitin-like modifier FAT10; biodegradable PLGA microspheres as vaccines and immunotherapeutics
Dr. Michael Basler

E-Mail Website
Co-Guest Editor
Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany
Interests: antigen processing and presentation; proteasome; immunoproteasome; viral infection; autoimmunity

Special Issue Information

Dear Colleagues,

The immunoproteasome is a cytokine-inducible variant of the standard proteasome in which the catalytically active subunits β1, β2, and β5 are replaced by the subunits β1i (LMP2), β2i (MECL-1), and β5i (LMP7). This subunit replacement changes the cleavage preferences of the proteasome and largely affects the generation of peptide ligands of MHC class I molecules. After 20 years of intensive study of the role of the immunoproteasome in antigen processing, 10 years ago, it was discovered that the immunoproteasome fulfills additional functions that are unrelated to antigen processing. With the help of immunoproteasome-selective inhibitors and gene-targeted mice, it could be shown that immunoproteasomes promote the differentiation of pro-inflammatory T helper cell subsets (Th1, Th17) and the production of pro-inflammatory cytokines (e.g., interferons, TNF, IL-6, IL-17, IL-23). These are involved in the development and persistence of autoimmune diseases, which may explain why immunoproteasome inhibition suppresses numerous autoimmune diseases as well as the chronic rejection of allotransplants in pre-clinical models. Excitingly, immunoproteasome inhibitors are presently tested as therapeutics against autoimmune diseases and cancer in humans. The almost exclusive expression of immunoproteasomes in virtually all types of immune cells poses questions about a potential special function of immunoproteasomes in leukocytes, which is currently being investigated. The renewed interest in immunoproteasome function is the impetus for compiling this Special Issue, which is exclusively dedicated to immunoproteasome research. Topics that will be covered in this issue include:

  • Structure—function relationship of the immunoproteasome;
  • Selective association of the immunoproteasome with proteasome regulators;
  • Functional differences between standard, intermediate, and immunoproteasomes;
  • The immunoproteasome in antigen processing and presentation;
  • The role of the immunoproteasome in proteostasis;
  • The evolution of the immunoproteasome;
  • The regulation of immunoproteasome expression;
  • The impact of the immunoproteasome on T cell activation and differentiation;
  • The function of the immunoproteasome in inflammation;
  • The therapeutic potential of immunoproteasome inhibitors in autoimmunity, inflammatory diseases, and cancer;
  • Interference with transplant rejection by immunoproteasome inhibitors;
  • The development of immunoproteasome selective inhibitors;
  • The clinical achievements obtained with immunoproteasome inhibitors.

Prof. Dr. Marcus Groettrup
Dr. Michael Basler
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunoproteasome
  • ubiquitin
  • protein degradation
  • antigen processing
  • MHC class I
  • T helper cell differentiation
  • cytokines
  • autoimmunity
  • transplantation
  • immunosuppression

Published Papers (13 papers)

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Research

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25 pages, 7956 KiB  
Article
Establishing 20S Proteasome Genetic, Translational and Post-Translational Status from Precious Biological and Patient Samples with Top-Down MS
by Angelique Sanchez Dafun, Dušan Živković, Stephen Adonai Leon-Icaza, Sophie Möller, Carine Froment, Delphine Bonnet, Adriana Almeida de Jesus, Laurent Alric, Muriel Quaranta-Nicaise, Audrey Ferrand, Céline Cougoule, Etienne Meunier, Odile Burlet-Schiltz, Frédéric Ebstein, Raphaela Goldbach-Mansky, Elke Krüger, Marie-Pierre Bousquet and Julien Marcoux
Cells 2023, 12(6), 844; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12060844 - 08 Mar 2023
Cited by 1 | Viewed by 2007
Abstract
The mammalian 20S catalytic core of the proteasome is made of 14 different subunits (α1-7 and β1-7) but exists as different subtypes depending on the cell type. In immune cells, for instance, constitutive catalytic proteasome subunits can be replaced by the so-called immuno-catalytic [...] Read more.
The mammalian 20S catalytic core of the proteasome is made of 14 different subunits (α1-7 and β1-7) but exists as different subtypes depending on the cell type. In immune cells, for instance, constitutive catalytic proteasome subunits can be replaced by the so-called immuno-catalytic subunits, giving rise to the immunoproteasome. Proteasome activity is also altered by post-translational modifications (PTMs) and by genetic variants. Immunochemical methods are commonly used to investigate these PTMs whereby protein-tagging is necessary to monitor their effect on 20S assembly. Here, we present a new miniaturized workflow combining top-down and bottom-up mass spectrometry of immunopurified 20S proteasomes that analyze the proteasome assembly status as well as the full proteoform footprint, revealing PTMs, mutations, single nucleotide polymorphisms (SNPs) and induction of immune-subunits in different biological samples, including organoids, biopsies and B-lymphoblastoid cell lines derived from patients with proteasome-associated autoinflammatory syndromes (PRAAS). We emphasize the benefits of using top-down mass spectrometry in preserving the endogenous conformation of protein modifications, while enabling a rapid turnaround (1 h run) and ensuring high sensitivity (1–2 pmol) and demonstrate its capacity to semi-quantify constitutive and immune proteasome subunits. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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15 pages, 2213 KiB  
Article
Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors
by Andrej Besse, Marianne Kraus, Max Mendez-Lopez, Elmer Maurits, Herman S. Overkleeft, Christoph Driessen and Lenka Besse
Cells 2022, 11(5), 838; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050838 - 01 Mar 2022
Cited by 1 | Viewed by 2422
Abstract
Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells [...] Read more.
Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome β5i, respectively. At the same time, LU102, a proteasome β2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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19 pages, 1198 KiB  
Article
Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads
by Levente Kollár, Martina Gobec, Matic Proj, Lara Smrdel, Damijan Knez, Tímea Imre, Ágnes Gömöry, László Petri, Péter Ábrányi-Balogh, Dorottya Csányi, György G. Ferenczy, Stanislav Gobec, Izidor Sosič and György M. Keserű
Cells 2021, 10(12), 3431; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123431 - 06 Dec 2021
Cited by 6 | Viewed by 3279
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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21 pages, 2260 KiB  
Article
Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study
by Ilona Elisabeth Kammerl, Claudia Flexeder, Stefan Karrasch, Barbara Thorand, Margit Heier, Annette Peters, Holger Schulz and Silke Meiners
Cells 2021, 10(12), 3336; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123336 - 28 Nov 2021
Cited by 3 | Viewed by 2354
Abstract
Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed [...] Read more.
Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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12 pages, 1757 KiB  
Article
High Immunoproteasome Activity and sXBP1 in Pediatric Precursor B-ALL Predicts Sensitivity towards Proteasome Inhibitors
by Lenka Besse, Andrej Besse, Marianne Kraus, Elmer Maurits, Herman S. Overkleeft, Beat Bornhauser, Jean-Pierre Bourquin and Christoph Driessen
Cells 2021, 10(11), 2853; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112853 - 22 Oct 2021
Cited by 2 | Viewed by 1895
Abstract
Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify [...] Read more.
Proteasome inhibitors (PIs) are approved backbone treatments in multiple myeloma. More recently, inhibition of proteasome activity with the PI bortezomib has been clinically evaluated as a novel treatment strategy in pediatric acute lymphoblastic leukemia (ALL). However, we lack a marker that could identify ALL patients responding to PI-based therapy. By using a set of activity-based proteasome probes in conjunction with cytotoxicity assays, we show that B-cell precursor ALL (BCP-ALL), in contrast to T-ALL, demonstrates an increased activity of immunoproteasome over constitutive proteasome, which correlates with high ex vivo sensitivity to the PIs bortezomib and ixazomib. The novel selective PI LU015i-targeting immunoproteasome β5i induces cytotoxicity in BCP-ALL containing high β5i activity, confirming immunoproteasome activity as a novel therapeutic target in BCP-ALL. At the same time, cotreatment with β2-selective proteasome inhibitors can sensitize T-ALL to currently available PIs, as well as to β5i selective PI. In addition, levels of total and spliced forms of XBP1 differ between BCP-ALL and T-ALL, and only in BCP-ALL does high-spliced XBP1 correlate with sensitivity to bortezomib. Thus, in BCP-ALL, high immunoproteasome activity may serve as a predictive marker for PI-based treatment options, potentially combined with XBP1 analyses. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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Review

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16 pages, 1318 KiB  
Review
The Molecular Mechanisms Governing the Assembly of the Immuno- and Thymoproteasomes in the Presence of Constitutive Proteasomes
by Ayaka Watanabe, Hideki Yashiroda, Satoshi Ishihara, Megan Lo and Shigeo Murata
Cells 2022, 11(9), 1580; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091580 - 07 May 2022
Cited by 5 | Viewed by 2469
Abstract
The proteasome is a large protein complex responsible for proteolysis in cells. Though the proteasome is widely conserved in all eukaryotes, vertebrates additionally possess tissue-specific proteasomes, termed immunoproteasomes and thymoproteasomes. These specialized proteasomes diverge from constitutive proteasomes in the makeup of their catalytic [...] Read more.
The proteasome is a large protein complex responsible for proteolysis in cells. Though the proteasome is widely conserved in all eukaryotes, vertebrates additionally possess tissue-specific proteasomes, termed immunoproteasomes and thymoproteasomes. These specialized proteasomes diverge from constitutive proteasomes in the makeup of their catalytic 20S core particle (CP), whereby the constitutive β1, β2, and β5 catalytic subunits are replaced by β1i, β2i, and β5i in immunoproteasomes, or β1i, β2i, and β5t in thymoproteasomes. However, as constitutive β1, β2, and β5 are also present in tissues and cells expressing immuno- and thymoproteasomes, the specialized proteasomes must be able to selectively incorporate their specific subunits. Here, we review the mechanisms governing the assembly of constitutive and specialized proteasomes elucidated thus far. Studies have revealed that β1i and β2i are added onto the α-ring of the CP prior to the other β subunits. Furthermore, β5i and β5t can be incorporated independent of β4, whereas constitutive β5 incorporation is dependent on β4. These mechanisms allow the immuno- and thymoproteasomes to integrate tissue-specific β-subunits without contamination from constitutive β1, β2, and β5. We end the review with a brief discussion on the diseases caused by mutations to the immunoproteasome and the proteins involved with its assembly. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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26 pages, 2278 KiB  
Review
Functional Differences between Proteasome Subtypes
by Joanna Abi Habib, Julie Lesenfants, Nathalie Vigneron and Benoit J. Van den Eynde
Cells 2022, 11(3), 421; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030421 - 26 Jan 2022
Cited by 19 | Viewed by 5918
Abstract
Four proteasome subtypes are commonly present in mammalian tissues: standard proteasomes, which contain the standard catalytic subunits β1, β2 and β5; immunoproteasomes containing the immuno-subunits β1i, β2i and β5i; and two intermediate proteasomes, containing a mix of standard and immuno-subunits. Recent studies revealed [...] Read more.
Four proteasome subtypes are commonly present in mammalian tissues: standard proteasomes, which contain the standard catalytic subunits β1, β2 and β5; immunoproteasomes containing the immuno-subunits β1i, β2i and β5i; and two intermediate proteasomes, containing a mix of standard and immuno-subunits. Recent studies revealed the expression of two tissue-specific proteasome subtypes in cortical thymic epithelial cells and in testes: thymoproteasomes and spermatoproteasomes. In this review, we describe the mechanisms that enable the ATP- and ubiquitin-dependent as well as the ATP- and ubiquitin-independent degradation of proteins by the proteasome. We focus on understanding the role of the different proteasome subtypes in maintaining protein homeostasis in normal physiological conditions through the ATP- and ubiquitin-dependent degradation of proteins. Additionally, we discuss the role of each proteasome subtype in the ATP- and ubiquitin-independent degradation of disordered proteins. We also discuss the role of the proteasome in the generation of peptides presented by MHC class I molecules and the implication of having different proteasome subtypes for the peptide repertoire presented at the cell surface. Finally, we discuss the role of the immunoproteasome in immune cells and its modulation as a potential therapy for autoimmune diseases. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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11 pages, 1469 KiB  
Review
Discovery and Early Clinical Development of Selective Immunoproteasome Inhibitors
by Christopher J. Kirk, Tony Muchamuel, Jinhai Wang and R. Andrea Fan
Cells 2022, 11(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010009 - 21 Dec 2021
Cited by 14 | Viewed by 3320
Abstract
Inhibitors of the proteolytic activity of the 20S proteasome have transformed the treatment of multiple B-cell malignancies. These agents have also been employed with success in the treatment of patients with autoimmune diseases and immune-mediated disorders. However, new agents are needed to fully [...] Read more.
Inhibitors of the proteolytic activity of the 20S proteasome have transformed the treatment of multiple B-cell malignancies. These agents have also been employed with success in the treatment of patients with autoimmune diseases and immune-mediated disorders. However, new agents are needed to fully unlock the potential of proteasome inhibitors as immunomodulatory drugs. The discovery that selective inhibitors of the immunoproteasome possess broad anti-inflammatory activity in preclinical models has led to the progression of multiple compounds to clinical trials. This review focuses on the anti-inflammatory potential of immunoproteasome inhibition and the early development of KZR-616, the first selective inhibitor of the immunoproteasome to reach clinical testing. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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22 pages, 1275 KiB  
Review
The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer
by Satyendra Chandra Tripathi, Disha Vedpathak and Edwin Justin Ostrin
Cells 2021, 10(12), 3587; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123587 - 20 Dec 2021
Cited by 13 | Viewed by 5514
Abstract
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. [...] Read more.
Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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16 pages, 1451 KiB  
Review
The Function of Immunoproteasomes—An Immunologists’ Perspective
by Bart L. van den Eshof, Lobna Medfai, Emanuele Nolfi, Magdalena Wawrzyniuk and Alice J. A. M. Sijts
Cells 2021, 10(12), 3360; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123360 - 30 Nov 2021
Cited by 7 | Viewed by 2843
Abstract
Proteasomes are responsible for intracellular proteolysis and play an important role in cellular protein homeostasis. Cells of the immune system assemble a specialized form of proteasomes, known as immunoproteasomes, in which the constitutive catalytic sites are replaced for cytokine-inducible homologues. While immunoproteasomes may [...] Read more.
Proteasomes are responsible for intracellular proteolysis and play an important role in cellular protein homeostasis. Cells of the immune system assemble a specialized form of proteasomes, known as immunoproteasomes, in which the constitutive catalytic sites are replaced for cytokine-inducible homologues. While immunoproteasomes may fulfill all standard proteasome’ functions, they seem specially adapted for a role in MHC class I antigen processing and CD8+ T-cell activation. In this way, they may contribute to CD8+ T-cell-mediated control of intracellular infections, but also to the immunopathogenesis of autoimmune diseases. Starting at the discovery of its catalytic subunits in the genome, here, we review the observations shaping our current understanding of immunoproteasome function, and the consequential novel opportunities for immune intervention. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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18 pages, 1457 KiB  
Review
On the Role of the Immunoproteasome in Protein Homeostasis
by Michael Basler and Marcus Groettrup
Cells 2021, 10(11), 3216; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113216 - 18 Nov 2021
Cited by 23 | Viewed by 3484
Abstract
Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic [...] Read more.
Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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21 pages, 20060 KiB  
Review
A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential
by Eva M. Huber and Michael Groll
Cells 2021, 10(8), 1929; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081929 - 29 Jul 2021
Cited by 14 | Viewed by 3653
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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21 pages, 1207 KiB  
Review
Immunoproteasome Function in Normal and Malignant Hematopoiesis
by Nuria Tubío-Santamaría, Frédéric Ebstein, Florian H. Heidel and Elke Krüger
Cells 2021, 10(7), 1577; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071577 - 22 Jun 2021
Cited by 16 | Viewed by 4741
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Immunoproteasome in Health and Disease)
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