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The Assembly and Function of Proteasomes in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 17266

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Special Issue Editors

Dr. Robert J. Tomko

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Guest Editor

College of Medicine, Florida State University, Tallahassee, USA
Interests: proteasome; ubiquitin; proteolysis; deubiquitinase; assembly; AAA+ ATPase

Dr. Soyeon Park

E-Mail Website
Guest Editor

Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, USA
Interests: proteasome; molecular chaperones; AAA+ ATPase; ubiquitin

Special Issue Information

Dear Colleagues,

The 26S proteasome is the largest and most complicated protease in eukaryotes. This fascinating molecular machine must identify, capture, and process specific substrates amidst a virtual sea of other proteins with exceptional selectivity and fidelity to maintain cell health. Proteasomal proteolysis touches virtually every facet of biology and is deregulated in cancers, neurodegenerative diseases, autoimmune disorders, and diabetes. Although proteasomes were discovered over 30 years ago, new and unexpected twists in our understanding of proteasome biology continue to emerge. This Special Issue will focus on the assembly, function, and regulation of the proteasome both under physiological and pathological conditions. Original manuscripts and reviews covering any aspect proteasome biology are very welcome.

Dr. Robert J. Tomko
Dr. Soyeon Park
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

proteasome
assembly
AAA+ ATPase
proteolysis
ubiquitin

Published Papers (6 papers)

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Research

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10 pages, 2173 KiB

Open AccessArticle

The 26S Proteasome Switches between ATP-Dependent and -Independent Mechanisms in Response to Substrate Ubiquitination

by Abramo J. Manfredonia and Daniel A. Kraut

Biomolecules 2022, 12(6), 750; https://doi.org/10.3390/biom12060750 - 26 May 2022

Cited by 1 | Viewed by 2216

Abstract

The ubiquitin–proteasome system is responsible for the bulk of protein degradation in eukaryotic cells. Proteins are generally targeted to the 26S proteasome through the attachment of polyubiquitin chains. Several proteins also contain ubiquitin-independent degrons (UbIDs) that allow for proteasomal targeting without the need for ubiquitination. Our laboratory previously showed that UbID substrates are less processively degraded than ubiquitinated substrates, but the mechanism underlying this difference remains unclear. We therefore designed two model substrates containing both a ubiquitination site and a UbID for a more direct comparison. We found UbID degradation to be overall less robust, with complete degradation only occurring with loosely folded substrates. UbID degradation was unaffected by the nonhydrolyzable ATP analog ATPγS, indicating that UbID degradation proceeds in an ATP-independent manner. Stabilizing substrates halted UbID degradation, indicating that the proteasome can only capture UbID substrates if they are already at least transiently unfolded, as confirmed using native-state proteolysis. The 26S proteasome therefore switches between ATP-independent weak degradation and ATP-dependent robust unfolding and degradation depending on whether or not the substrate is ubiquitinated. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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Graphical abstract

15 pages, 2825 KiB

Open AccessEditor’s ChoiceArticle

Interaction with the Assembly Chaperone Ump1 Promotes Incorporation of the β7 Subunit into Half-Proteasome Precursor Complexes Driving Their Dimerization

by Jessica Zimmermann, Paula C. Ramos and R. Jürgen Dohmen

Biomolecules 2022, 12(2), 253; https://doi.org/10.3390/biom12020253 - 4 Feb 2022

Cited by 5 | Viewed by 2038

Abstract

Biogenesis of the eukaryotic 20S proteasome core particle (PC) is a complex process assisted by specific chaperones absent from the active complex. The first identified chaperone, Ump1, was found in a precursor complex (PC) called 15S PC. Yeast cells lacking Ump1 display strong defects in the autocatalytic processing of β subunits, and consequently have lower proteolytic activity. Here, we dissect an important interaction of Ump1 with the β7 subunit that is critical for proteasome biogenesis. Functional domains of Ump1 and the interacting proteasome subunit β7 were mapped, and the functional consequences of their deletion or mutation were analyzed. Cells in which the first sixteen Ump1 residues were deleted display growth phenotypes similar to ump1∆, but massively accumulate 15S PC and distinct proteasome intermediate complexes containing the truncated protein. The viability of these cells depends on the transcription factor Rpn4. Remarkably, β7 subunit overexpression re-established viability in the absence of Rpn4. We show that an N-terminal domain of Ump1 and the propeptide of β7 promote direct interaction of the two polypeptides in vitro. This interaction is of critical importance for the recruitment of β7 precursor during proteasome assembly, a step that drives dimerization of 15S PCs and the formation of 20S CPs. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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19 pages, 1704 KiB

Open AccessArticle

Proteasome Inhibition Is an Effective Treatment Strategy for Microsporidia Infection in Honey Bees

by Emily M. Huntsman, Rachel M. Cho, Helen V. Kogan, Nora K. McNamara-Bordewick, Robert J. Tomko, Jr. and Jonathan W. Snow

Biomolecules 2021, 11(11), 1600; https://doi.org/10.3390/biom11111600 - 29 Oct 2021

Cited by 7 | Viewed by 2492

Abstract

The microsporidia Nosema ceranae is an obligate intracellular parasite that causes honey bee mortality and contributes to colony collapse. Fumagillin is presently the only pharmacological control for N. ceranae infections in honey bees. Resistance is already emerging, and alternative controls are critically needed. Nosema spp. exhibit increased sensitivity to heat shock, a common proteotoxic stress. Thus, we hypothesized that targeting the Nosema proteasome, the major protease removing misfolded proteins, might be effective against N. ceranae infections in honey bees. Nosema genome analysis and molecular modeling revealed an unexpectedly compact proteasome apparently lacking multiple canonical subunits, but with highly conserved proteolytic active sites expected to be receptive to FDA-approved proteasome inhibitors. Indeed, N. ceranae were strikingly sensitive to pharmacological disruption of proteasome function at doses that were well tolerated by honey bees. Thus, proteasome inhibition is a novel candidate treatment strategy for microsporidia infection in honey bees. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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Review

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11 pages, 632 KiB

Open AccessFeature PaperReview

Allostery Modulates Interactions between Proteasome Core Particles and Regulatory Particles

by Philip Coffino and Yifan Cheng

Biomolecules 2022, 12(6), 764; https://doi.org/10.3390/biom12060764 - 30 May 2022

Cited by 3 | Viewed by 1701

Abstract

Allostery—regulation at distant sites is a key concept in biology. The proteasome exhibits multiple forms of allosteric regulation. This regulatory communication can span a distance exceeding 100 Ångstroms and can modulate interactions between the two major proteasome modules: its core particle and regulatory complexes. Allostery can further influence the assembly of the core particle with regulatory particles. In this focused review, known and postulated interactions between these proteasome modules are described. Allostery may explain how cells build and maintain diverse populations of proteasome assemblies and can provide opportunities for therapeutic interventions. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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Figure 1

22 pages, 1783 KiB

Open AccessFeature PaperReview

Biology of the Extracellular Proteasome

by Gili Ben-Nissan, Naama Katzir, Maria Gabriella Füzesi-Levi and Michal Sharon

Biomolecules 2022, 12(5), 619; https://doi.org/10.3390/biom12050619 - 21 Apr 2022

Cited by 11 | Viewed by 3545

Abstract

Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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Figure 1

16 pages, 701 KiB

Open AccessReview

Localized Proteasomal Degradation: From the Nucleus to Cell Periphery

by Xing Guo

Biomolecules 2022, 12(2), 229; https://doi.org/10.3390/biom12020229 - 29 Jan 2022

Cited by 14 | Viewed by 4431

Abstract

The proteasome is responsible for selective degradation of most cellular proteins. Abundantly present in the cell, proteasomes not only diffuse in the cytoplasm and the nucleus but also associate with the chromatin, cytoskeleton, various membranes and membraneless organelles/condensates. How and why the proteasome gets to these specific subcellular compartments remains poorly understood, although increasing evidence supports the hypothesis that intracellular localization may have profound impacts on the activity, substrate accessibility and stability/integrity of the proteasome. In this short review, I summarize recent advances on the functions, regulations and targeting mechanisms of proteasomes, especially those localized to the nuclear condensates and membrane structures of the cell, and I discuss the biological significance thereof in mediating compartmentalized protein degradation. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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