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Biomolecules
Special Issues
Regulating Proteasome Activity
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Regulating Proteasome Activity

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 42283

Special Issue Editors

Prof. Dr. Paolo Cascio

E-Mail Website
Guest Editor
Department of Veterinary Sciences, University of Turin, L.go P. Braccini 2, 10095 Grugliasco, Italy
Interests: proteasome and immunoproteasome; PA28αβ and γ; ubiquitin–proteasome system; MHC-class I antigen presentation; antigenic peptides; proteasome inhibitors; proteostasis; proteotoxic stress and cancer
Prof. Dr. Gunnar Dittmar

E-Mail Website
Guest Editor
Proteomics of Cellular Signaling, Luxembourg Institute of Health, Rue Thomas Edison 1A-B, L-1445 Strassen, Luxembourg
Interests: proteomics; degradomics; interactomics; ubiquitin; post-translational modifications; PTM; intrinsically disordered regions; IDR; protein stability

Special Issue Information

Dear Colleagues,

Strictly controlled degradation of the proteome is a key factor in maintaining cellular homeostasis and allows for a rapid and effective response to stress challenges of different nature. The central element of the regulatory degradative network that integrates different stimuli and signals is the proteasome, a macromolecular machine designed to selectively remove specific proteins according to the variable needs of the cell. Not surprisingly, given the extreme complexity and interdependence of the pathways involved, the proteolytic system has evolved with a modular organization, based on a central hydrolytic element, Proteasome 20S, to which alternative regulatory modules can associate to fine-tune its activity. The perturbation of this delicate network is involved in the onset of various pathological conditions, and in recent years, the strategies for modulating this proteolytic pathway have proven to be extremely useful for both research and therapeutic purposes.

This Special Issue will focus on all aspects of the properties and regulations of proteasomes, including functions and mechanisms of action of physiological proteasome interactors, as well as pharmacological molecules that activate or inhibit its enzymatic activities. Original research articles and reviews summarizing recent crucial advances in the field are welcome.

Prof. Dr. Paolo Cascio
Prof. Dr. Gunnar Dittmar
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

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

  • Proteasomes
  • Proteasome-dependent proteolysis
  • Proteasomal degradation
  • Ubiquitin–proteasome system (UPS)
  • Ubiquitin
  • ATP-dependent proteolysis
  • Proteasome activators
  • Proteasome inhibitors
  • Proteasome enzymatic activities
  • Proteasome active sites
  • Proteotoxic stress
  • MHC class-I antigen presentation
  • Proteasome associated deubiquitination
  • Proteasome and peptides

Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 184 KiB  
Editorial
Regulating Proteasome Activity
by Paolo Cascio and Gunnar Dittmar
Biomolecules 2022, 12(3), 343; https://doi.org/10.3390/biom12030343 - 23 Feb 2022
Viewed by 1432
Abstract
Strictly controlled degradation of the proteome is a key factor in maintaining cellular homeostasis and allows a rapid and effective response to a variety of different stress challenges [...] Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)

Research

Jump to: Editorial, Review, Other

20 pages, 4626 KiB  
Article
Insulin-Degrading Enzyme Is a Non Proteasomal Target of Carfilzomib and Affects the 20S Proteasome Inhibition by the Drug
by Grazia Raffaella Tundo, Diego Sbardella, Francesco Oddone, Giuseppe Grasso, Stefano Marini, Maria Grazia Atzori, Anna Maria Santoro, Danilo Milardi, Francesco Bellia, Gabriele Macari, Grazia Graziani, Fabio Polticelli, Paolo Cascio, Mariacristina Parravano and Massimo Coletta
Biomolecules 2022, 12(2), 315; https://doi.org/10.3390/biom12020315 - 16 Feb 2022
Cited by 3 | Viewed by 2097
Abstract
Carfilzomib is a last generation proteasome inhibitor (PI) with proven clinical efficacy in the treatment of relapsed/refractory multiple myeloma. This drug is considered to be extremely specific in inhibiting the chymotrypsin-like activity of the 20S proteasome, encoded by the β5 subunit, overcoming some [...] Read more.
Carfilzomib is a last generation proteasome inhibitor (PI) with proven clinical efficacy in the treatment of relapsed/refractory multiple myeloma. This drug is considered to be extremely specific in inhibiting the chymotrypsin-like activity of the 20S proteasome, encoded by the β5 subunit, overcoming some bortezomib limitations, the first PI approved for multiple myeloma therapy which is however burdened by a significant toxicity profile, due also to its off-target effects. Here, molecular approaches coupled with molecular docking studies have been used to unveil that the Insulin-Degrading Enzyme, a ubiquitous and highly conserved Zn2+ peptidase, often found to associate with proteasome in cell-based models, is targeted by carfilzomib in vitro. The drug behaves as a modulator of IDE activity, displaying an inhibitory effect over 10-fold lower than for the 20S. Notably, the interaction of IDE with the 20S enhances in vitro the inhibitory power of carfilzomib on proteasome, so that the IDE-20S complex is an even better target of carfilzomib than the 20S alone. Furthermore, IDE gene silencing after delivery of antisense oligonucleotides (siRNA) significantly reduced carfilzomib cytotoxicity in rMC1 cells, a validated model of Muller glia, suggesting that, in cells, the inhibitory activity of this drug on cell proliferation is somewhat linked to IDE and, possibly, also to its interaction with proteasome. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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32 pages, 7416 KiB  
Article
The Proteasome Activators Blm10/PA200 Enhance the Proteasomal Degradation of N-Terminal Huntingtin
by Azzam Aladdin, Yanhua Yao, Ciyu Yang, Günther Kahlert, Marvi Ghani, Nikolett Király, Anita Boratkó, Karen Uray, Gunnar Dittmar and Krisztina Tar
Biomolecules 2020, 10(11), 1581; https://doi.org/10.3390/biom10111581 - 20 Nov 2020
Cited by 9 | Viewed by 4049
Abstract
The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin- and ATP-independent manner. Furthermore, [...] Read more.
The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin- and ATP-independent manner. Furthermore, PA200 also participates in the degradation of acetylated histones. In our study, we use a combination of yeast and human cell systems to investigate the role of Blm10/PA200 in the degradation of N-terminal Huntingtin fragments (N-Htt). We demonstrate that the human PA200 binds to N-Htt. The loss of Blm10 in yeast or PA200 in human cells results in increased mutant N-Htt aggregate formation and elevated cellular toxicity. Furthermore, Blm10 in vitro accelerates the proteasomal degradation of soluble N-Htt. Collectively, our data suggest N-Htt as a new substrate for Blm10/PA200-proteasomes and point to new approaches in Huntington’s disease (HD) research. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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Review

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21 pages, 3531 KiB  
Review
Site-Specific Proteasome Inhibitors
by Alexei F. Kisselev
Biomolecules 2022, 12(1), 54; https://doi.org/10.3390/biom12010054 - 31 Dec 2021
Cited by 25 | Viewed by 3578
Abstract
Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, [...] Read more.
Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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42 pages, 2047 KiB  
Review
Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation
by Stefanie Haberecht-Müller, Elke Krüger and Jens Fielitz
Biomolecules 2021, 11(9), 1327; https://doi.org/10.3390/biom11091327 - 08 Sep 2021
Cited by 38 | Viewed by 5335
Abstract
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein [...] Read more.
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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17 pages, 1911 KiB  
Review
Gatekeepers of the Gut: The Roles of Proteasomes at the Gastrointestinal Barrier
by Gayatree Mohapatra, Avital Eisenberg-Lerner and Yifat Merbl
Biomolecules 2021, 11(7), 989; https://doi.org/10.3390/biom11070989 - 05 Jul 2021
Cited by 7 | Viewed by 2847
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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22 pages, 2069 KiB  
Review
Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation
by Alfred L. Goldberg, Hyoung Tae Kim, Donghoon Lee and Galen Andrew Collins
Biomolecules 2021, 11(6), 779; https://doi.org/10.3390/biom11060779 - 22 May 2021
Cited by 18 | Viewed by 6012
Abstract
Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become [...] Read more.
Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14’s UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome’s activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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23 pages, 6848 KiB  
Review
TRIM32: A Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis
by Simranjot Bawa, Rosanna Piccirillo and Erika R. Geisbrecht
Biomolecules 2021, 11(3), 408; https://doi.org/10.3390/biom11030408 - 10 Mar 2021
Cited by 12 | Viewed by 3638
Abstract
Human tripartite motif family of proteins 32 (TRIM32) is a ubiquitous multifunctional protein that has demonstrated roles in differentiation, muscle physiology and regeneration, and tumor suppression. Mutations in TRIM32 result in two clinically diverse diseases. A mutation in the B-box domain gives rise [...] Read more.
Human tripartite motif family of proteins 32 (TRIM32) is a ubiquitous multifunctional protein that has demonstrated roles in differentiation, muscle physiology and regeneration, and tumor suppression. Mutations in TRIM32 result in two clinically diverse diseases. A mutation in the B-box domain gives rise to Bardet–Biedl syndrome (BBS), a disease whose clinical presentation shares no muscle pathology, while mutations in the NHL (NCL-1, HT2A, LIN-41) repeats of TRIM32 causes limb-girdle muscular dystrophy type 2H (LGMD2H). TRIM32 also functions as a tumor suppressor, but paradoxically is overexpressed in certain types of cancer. Recent evidence supports a role for TRIM32 in glycolytic-mediated cell growth, thus providing a possible mechanism for TRIM32 in the accumulation of cellular biomass during regeneration and tumorigenesis, including in vitro and in vivo approaches, to understand the broad spectrum of TRIM32 functions. A special emphasis is placed on the utility of the Drosophila model, a unique system to study glycolysis and anabolic pathways that contribute to the growth and homeostasis of both normal and tumor tissues. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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23 pages, 2441 KiB  
Review
PA28γ: New Insights on an Ancient Proteasome Activator
by Paolo Cascio
Biomolecules 2021, 11(2), 228; https://doi.org/10.3390/biom11020228 - 05 Feb 2021
Cited by 30 | Viewed by 4331
Abstract
PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero [...] Read more.
PA28 (also known as 11S, REG or PSME) is a family of proteasome regulators whose members are widely present in many of the eukaryotic supergroups. In jawed vertebrates they are represented by three paralogs, PA28α, PA28β, and PA28γ, which assemble as heptameric hetero (PA28αβ) or homo (PA28γ) rings on one or both extremities of the 20S proteasome cylindrical structure. While they share high sequence and structural similarities, the three isoforms significantly differ in terms of their biochemical and biological properties. In fact, PA28α and PA28β seem to have appeared more recently and to have evolved very rapidly to perform new functions that are specifically aimed at optimizing the process of MHC class I antigen presentation. In line with this, PA28αβ favors release of peptide products by proteasomes and is particularly suited to support adaptive immune responses without, however, affecting hydrolysis rates of protein substrates. On the contrary, PA28γ seems to be a slow-evolving gene that is most similar to the common ancestor of the PA28 activators family, and very likely retains its original functions. Notably, PA28γ has a prevalent nuclear localization and is involved in the regulation of several essential cellular processes including cell growth and proliferation, apoptosis, chromatin structure and organization, and response to DNA damage. In striking contrast with the activity of PA28αβ, most of these diverse biological functions of PA28γ seem to depend on its ability to markedly enhance degradation rates of regulatory protein by 20S proteasome. The present review will focus on the molecular mechanisms and biochemical properties of PA28γ, which are likely to account for its various and complex biological functions and highlight the common features with the PA28αβ paralog. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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15 pages, 2917 KiB  
Review
Structural Insights into Substrate Recognition and Processing by the 20S Proteasome
by Indrajit Sahu and Michael H. Glickman
Biomolecules 2021, 11(2), 148; https://doi.org/10.3390/biom11020148 - 24 Jan 2021
Cited by 32 | Viewed by 5287
Abstract
Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half [...] Read more.
Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half of all proteasomes in most eukaryotic cells are free 20S complexes, ubiquitin-independent protein degradation may coexist with ubiquitin-dependent degradation by the highly regulated 26S proteasome. This article reviews recent advances in our understanding of the biochemical and structural features that underlie the proteolytic mechanism of 20S proteasomes. The two outer α-rings of 20S proteasomes provide a number of potential docking sites for loosely folded polypeptides. The binding of a substrate can induce asymmetric conformational changes, trigger gate opening, and initiate its own degradation through a protease-driven translocation mechanism. Consequently, the substrate translocates through two additional narrow apertures augmented by the β-catalytic active sites. The overall pulling force through the two annuli results in a protease-like unfolding of the substrate and subsequent proteolysis in the catalytic chamber. Although both proteasomes contain identical β-catalytic active sites, the differential translocation mechanisms yield distinct peptide products. Nonoverlapping substrate repertoires and product outcomes rationalize cohabitation of both proteasome complexes in cells. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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Other

7 pages, 886 KiB  
Perspective
Analysis of the Dynamic Proteasome Structure by Cross-Linking Mass Spectrometry
by Marta L. Mendes and Gunnar Dittmar
Biomolecules 2021, 11(4), 505; https://doi.org/10.3390/biom11040505 - 27 Mar 2021
Cited by 3 | Viewed by 2253
Abstract
The 26S proteasome is a macromolecular complex that degrades proteins maintaining cell homeostasis; thus, determining its structure is a priority to understand its function. Although the 20S proteasome’s structure has been known for some years, the highly dynamic nature of the 19S regulatory [...] Read more.
The 26S proteasome is a macromolecular complex that degrades proteins maintaining cell homeostasis; thus, determining its structure is a priority to understand its function. Although the 20S proteasome’s structure has been known for some years, the highly dynamic nature of the 19S regulatory particle has presented a challenge to structural biologists. Advances in cryo-electron microscopy (cryo-EM) made it possible to determine the structure of the 19S regulatory particle and showed at least seven different conformational states of the proteasome. However, there are still many questions to be answered. Cross-linking mass spectrometry (CLMS) is now routinely used in integrative structural biology studies, and it promises to take integrative structural biology to the next level, answering some of these questions. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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