Special Issue "Proteasomes and Its Regulators"

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

Deadline for manuscript submissions: closed (31 March 2014)

Special Issue Editors

Guest Editor
Prof. Dr. Olivier Coux

Centre de Recherches de Biochimie Macromoléculaire (CRBM), CNRS-UMII UMR5237, Universités Montpellier 1 and 2, 1919 route de Mende, 34293 Montpellier cedex 05, France
Website | E-Mail
Interests: proteasome and its regulators; p53 and Cdc25B ubiquitylation and degradation
Guest Editor
Prof. Dr. Michael H. Glickman

Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel
Website | E-Mail
Interests: dynamic protein network responses, networks determining protein fate, turnover and homeostasis (proteostasis);Proteasome structure and function; Mechanistic aspects of protein degradation; ubiquitin-proteasome system; Charting the cellular ubiquitin-linkage profile

Special Issue Information

Dear Colleagues,

25 years after its official beginning in the literature, the proteasome is now recognized as a key regulator of cellular homeostasis, critical for the control of all biological processes. Yet, despite the rapid expansion of the scientific fields in which this fascinating complex (or more exactly family of complexes) has been shown to be involved, it is still often viewed by many biologists as a simple garbage can, largely solved and with no more hidden secrets.

With this special topic-focused compilation on “proteasome and its regulators”, freely accessible online from all over the world, we would like to provide to a general audience a large overview of the present state of our knowledge on this fascinating family of complexes. From what is clearly established to the many open questions that remain to be answered, our objective is to assemble a series of reviews or original articles that will constitute together a “proteasome encyclopedia” in which everyone could find up-to-date information in the different issues directly connected to proteasome biology.

We are thus welcoming any manuscript on the evolution, structure, assembly, mechanisms of action, regulation, or relationship to other biological processes, of the proteasome and its regulators.

We look forward to reading your contributions,

Prof. Michael H. Glickman
Prof. Dr. Olivier Coux
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 papers will be 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 quarterly 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 650 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.

Published Papers (17 papers)

View options order results:
result details:
Displaying articles 1-17
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle Redox-Regulated Pathway of Tyrosine Phosphorylation Underlies NF-κB Induction by an Atypical Pathway Independent of the 26S Proteasome
Biomolecules 2015, 5(1), 95-112; doi:10.3390/biom5010095
Received: 4 September 2014 / Revised: 25 November 2014 / Accepted: 28 January 2015 / Published: 9 February 2015
PDF Full-text (9796 KB) | HTML Full-text | XML Full-text
Abstract
Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of
[...] Read more.
Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of signaling events distinct from tyrosine phosphorylation of IκBα. To delineate roles for the ubiquitin-proteasome pathway in the phospho-tyrosine dependent mechanism of NF-κB induction, we employed the proteasome inhibitor, Aclacinomycin, and the phosphotyrosine phosphatase inhibitor, pervanadate (PV). Results from these studies demonstrate that phospho-IκBα (Tyr-42) is not subject to proteasomal degradation in a murine stromal epithelial cell line, confirming results previously reported. Correspondingly, proteasome inhibition had no discernable effect on the key signaling intermediaries, Src and ERK1/2, involved in the phospho-tyrosine mechanisms regulating PV-mediated activation of NF-κB. Consistent with previous reports, a significant redox imbalance leading to the activation of tyrosine kinases, as occurs with pervanadate, is required for the induction of NF-κB. Strikingly, our studies demonstrate that proteasome inhibition can potentiate oxidative stress associated with PV-stimulation without impacting kinase activation, however, other cellular implications for this increase in intracellular oxidation remain to be fully delineated. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessArticle Inhibitory Effect of b-AP15 on the 20S Proteasome
Biomolecules 2014, 4(4), 931-939; doi:10.3390/biom4040931
Received: 5 June 2014 / Revised: 5 August 2014 / Accepted: 23 September 2014 / Published: 14 October 2014
Cited by 1 | PDF Full-text (4262 KB) | HTML Full-text | XML Full-text
Abstract
The 26S proteasome is a cellular proteolytic complex containing 19S regulatory particles and the 20S core proteasome. It was reported that the small molecule b-AP15 targets the proteasome by inhibiting deubiquitination of the 19S regulatory particles of the proteasome complex. An investigation of
[...] Read more.
The 26S proteasome is a cellular proteolytic complex containing 19S regulatory particles and the 20S core proteasome. It was reported that the small molecule b-AP15 targets the proteasome by inhibiting deubiquitination of the 19S regulatory particles of the proteasome complex. An investigation of b-AP15 on the 20S proteasome core suggested that this compound can also inhibit the 20S proteasome with a potency equivalent to that found to inhibit the 19S regulatory particles. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessArticle Assembly Mechanisms of Specialized Core Particles of the Proteasome
Biomolecules 2014, 4(3), 662-677; doi:10.3390/biom4030662
Received: 3 April 2014 / Revised: 30 May 2014 / Accepted: 22 June 2014 / Published: 16 July 2014
Cited by 4 | PDF Full-text (2404 KB) | HTML Full-text | XML Full-text
Abstract
The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome
[...] Read more.
The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome has catalytic subunits β1i, β2i, and β5i replacing β1, β2, and β5 and enhances production of major histocompatibility complex I ligands. The thymoproteasome contains thymus-specific subunit β5t in place of β5 or β5i and plays a pivotal role in positive selection of CD8+ T cells. Here we investigate the assembly pathways of the specialized CPs and show that β1i and β2i are incorporated ahead of all the other β-subunits and that both β5i and β5t can be incorporated immediately after the assembly of β3 in the absence of β4, distinct from the assembly of the standard CP in which β-subunits are incorporated in the order of β2, β3, β4, β5, β6, β1, and β7. The propeptide of β5t is a key factor for this earlier incorporation, whereas the body sequence seems to be important for the earlier incorporation of β5i. This unique feature of β5t and β5i may account for preferential assembly of the immunoproteasome and the thymoproteasome over the standard type even when both the standard and specialized subunits are co-expressed. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Figures

Review

Jump to: Research

Open AccessReview Proteins Directly Interacting with Mammalian 20S Proteasomal Subunits and Ubiquitin-Independent Proteasomal Degradation
Biomolecules 2014, 4(4), 1140-1154; doi:10.3390/biom4041140
Received: 1 June 2014 / Revised: 25 November 2014 / Accepted: 11 December 2014 / Published: 19 December 2014
Cited by 4 | PDF Full-text (7351 KB) | HTML Full-text | XML Full-text
Abstract
The mammalian 20S proteasome is a heterodimeric cylindrical complex (α7β7β7α7), composed of four rings each composed of seven different α or β subunits with broad proteolytic activity. We review the mammalian proteins shown to directly interact with specific 20S proteasomal subunits and those
[...] Read more.
The mammalian 20S proteasome is a heterodimeric cylindrical complex (α7β7β7α7), composed of four rings each composed of seven different α or β subunits with broad proteolytic activity. We review the mammalian proteins shown to directly interact with specific 20S proteasomal subunits and those subjected to ubiquitin-independent proteasomal degradation (UIPD). The published reports of proteins that interact with specific proteasomal subunits, and others found on interactome databases and those that are degraded by a UIPD mechanism, overlap by only a few protein members. Therefore, systematic studies of the specificity of the interactions, the elucidation of the protein regions implicated in the interactions (that may or may not be followed by degradation) and competition experiments between proteins known to interact with the same proteasomal subunit, are needed. Those studies should provide a coherent picture of the molecular mechanisms governing the interactions of cellular proteins with proteasomal subunits, and their relevance to cell proteostasis and cell functioning. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Functions of the Proteasome on Chromatin
Biomolecules 2014, 4(4), 1026-1044; doi:10.3390/biom4041026
Received: 11 August 2014 / Revised: 11 September 2014 / Accepted: 10 November 2014 / Published: 21 November 2014
Cited by 8 | PDF Full-text (15823 KB) | HTML Full-text | XML Full-text
Abstract
The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur
[...] Read more.
The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur on chromatin. In this review, we discuss some of the ways in which proteasomes directly regulate the structure and function of chromatin and chromatin regulatory proteins, and how this influences gene transcription. We discuss lingering controversies in the field, the relative importance of proteolytic versus non-proteolytic proteasome activities in this process, and highlight areas that require further investigation. Our intention is to show that proteasomes are involved in major steps controlling the expression of the genetic information, that proteasomes use both proteolytic mechanisms and ATP-dependent protein remodeling to accomplish this task, and that much is yet to be learned about the full spectrum of ways that proteasomes influence the genome. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Proteasome Subtypes and Regulators in the Processing of Antigenic Peptides Presented by Class I Molecules of the Major Histocompatibility Complex
Biomolecules 2014, 4(4), 994-1025; doi:10.3390/biom4040994
Received: 30 July 2014 / Revised: 2 October 2014 / Accepted: 29 October 2014 / Published: 18 November 2014
Cited by 16 | PDF Full-text (397 KB) | HTML Full-text | XML Full-text
Abstract
The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these
[...] Read more.
The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these peptides escape degradation in the cytosol, are loaded onto class I molecules of the major histocompatibility complex (MHC) and displayed at the cell surface for scrutiny by the immune system. The proteasome therefore plays a key role for the immune system: it provides a continued sampling of intracellular proteins, so that CD8-positive T-lymphocytes can kill cells expressing viral or tumoral proteins. Consequently, the repertoire of peptides displayed by MHC class I molecules at the cell surface depends on proteasome activity, which may vary according to the presence of proteasome subtypes and regulators. Besides standard proteasomes, cells may contain immunoproteasomes, intermediate proteasomes and thymoproteasomes. Cells may also contain regulators of proteasome activity, such as the 19S, PA28 and PA200 regulators. Here, we review the effects of these proteasome subtypes and regulators on the production of antigenic peptides. We also discuss an unexpected function of the proteasome discovered through the study of antigenic peptides: its ability to splice peptides. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Nuclear Transport of Yeast Proteasomes
Biomolecules 2014, 4(4), 940-955; doi:10.3390/biom4040940
Received: 2 June 2014 / Revised: 18 August 2014 / Accepted: 26 September 2014 / Published: 20 October 2014
Cited by 7 | PDF Full-text (13375 KB) | HTML Full-text | XML Full-text
Abstract
Proteasomes are conserved protease complexes enriched in the nuclei of dividing yeast cells, a major site for protein degradation. If yeast cells do not proliferate and transit to quiescence, metabolic changes result in the dissociation of proteasomes into proteolytic core and regulatory complexes
[...] Read more.
Proteasomes are conserved protease complexes enriched in the nuclei of dividing yeast cells, a major site for protein degradation. If yeast cells do not proliferate and transit to quiescence, metabolic changes result in the dissociation of proteasomes into proteolytic core and regulatory complexes and their sequestration into motile cytosolic proteasome storage granuli. These granuli rapidly clear with the resumption of growth, releasing the stored proteasomes, which relocalize back to the nucleus to promote cell cycle progression. Here, I report on three models of how proteasomes are transported from the cytoplasm into the nucleus of yeast cells. The first model applies for dividing yeast and is based on the canonical pathway using classical nuclear localization sequences of proteasomal subcomplexes and the classical import receptor importin/karyopherin αβ. The second model applies for quiescent yeast cells, which resume growth and use Blm10, a HEAT-like repeat protein structurally related to karyopherin β, for nuclear import of proteasome core particles. In the third model, the fully-assembled proteasome is imported into the nucleus. Our still marginal knowledge about proteasome dynamics will inspire the discussion on how protein degradation by proteasomes may be regulated in different cellular compartments of dividing and quiescent eukaryotic cells. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Figures

Open AccessReview Cullin E3 Ligases and Their Rewiring by Viral Factors
Biomolecules 2014, 4(4), 897-930; doi:10.3390/biom4040897
Received: 21 April 2014 / Revised: 20 August 2014 / Accepted: 15 September 2014 / Published: 13 October 2014
Cited by 9 | PDF Full-text (51116 KB) | HTML Full-text | XML Full-text
Abstract
The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the
[...] Read more.
The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the expression of viral proteins capable of sequestering host ubiquitin E3 ligases and their regulators. In particular, many viruses hijack members of the Cullin-RING E3 Ligase (CRL) family. Viruses interact in many ways with CRLs in order to impact their ligase activity; one key recurring interaction involves re-directing CRL complexes to degrade host targets that are otherwise not degraded within host cells. Removal of host immune factors by this mechanism creates a more amenable cellular environment for viral propagation. To date, a small number of target host factors have been identified, many of which are degraded via a CRL-proteasome pathway. Substantial effort within the field is ongoing to uncover the identities of further host proteins targeted in this fashion and the underlying mechanisms driving their turnover by the UPS. Elucidation of these targets and mechanisms will provide appealing anti-viral therapeutic opportunities. This review is focused on the many methods used by viruses to perturb host CRLs, focusing on substrate sequestration and viral regulation of E3 activity. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Proteasome- and Ethanol-Dependent Regulation of HCV-Infection Pathogenesis
Biomolecules 2014, 4(4), 885-896; doi:10.3390/biom4040885
Received: 29 May 2014 / Revised: 5 August 2014 / Accepted: 16 September 2014 / Published: 29 September 2014
Cited by 4 | PDF Full-text (85 KB) | HTML Full-text | XML Full-text
Abstract
This paper reviews the role of the catabolism of HCV and signaling proteins in HCV protection and the involvement of ethanol in HCV-proteasome interactions. HCV specifically infects hepatocytes, and intracellularly expressed HCV proteins generate oxidative stress, which is further exacerbated by heavy drinking.
[...] Read more.
This paper reviews the role of the catabolism of HCV and signaling proteins in HCV protection and the involvement of ethanol in HCV-proteasome interactions. HCV specifically infects hepatocytes, and intracellularly expressed HCV proteins generate oxidative stress, which is further exacerbated by heavy drinking. The proteasome is the principal proteolytic system in cells, and its activity is sensitive to the level of cellular oxidative stress. Not only host proteins, but some HCV proteins are degraded by the proteasome, which, in turn, controls HCV propagation and is crucial for the elimination of the virus. Ubiquitylation of HCV proteins usually leads to the prevention of HCV propagation, while accumulation of undegraded viral proteins in the nuclear compartment exacerbates infection pathogenesis. Proteasome activity also regulates both innate and adaptive immunity in HCV-infected cells. In addition, the proteasome/immunoproteasome is activated by interferons, which also induce “early” and “late” interferon-sensitive genes (ISGs) with anti-viral properties. Cleaving viral proteins to peptides in professional immune antigen presenting cells and infected (“target”) hepatocytes that express the MHC class I-antigenic peptide complex, the proteasome regulates the clearance of infected hepatocytes by the immune system. Alcohol exposure prevents peptide cleavage by generating metabolites that impair proteasome activity, thereby providing escape mechanisms that interfere with efficient viral clearance to promote the persistence of HCV-infection. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Regulating the 20S Proteasome Ubiquitin-Independent Degradation Pathway
Biomolecules 2014, 4(3), 862-884; doi:10.3390/biom4030862
Received: 4 May 2014 / Revised: 27 August 2014 / Accepted: 5 September 2014 / Published: 23 September 2014
Cited by 50 | PDF Full-text (11581 KB) | HTML Full-text | XML Full-text
Abstract
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by the core 20S proteasome itself. Degradation by the 20S proteasome does not
[...] Read more.
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by the core 20S proteasome itself. Degradation by the 20S proteasome does not require ubiquitin tagging or the presence of the 19S regulatory particle; rather, it relies on the inherent structural disorder of the protein being degraded. Thus, proteins that contain unstructured regions due to oxidation, mutation, or aging, as well as naturally, intrinsically unfolded proteins, are susceptible to 20S degradation. Unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome, relatively little is known about the means by which 20S-mediated proteolysis is controlled. Here, we describe our current understanding of the regulatory mechanisms that coordinate 20S proteasome-mediated degradation, and highlight the gaps in knowledge that remain to be bridged. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Figures

Open AccessReview Particle-Rich Cytoplasmic Structure (PaCS): Identification, Natural History, Role in Cell Biology and Pathology
Biomolecules 2014, 4(3), 848-861; doi:10.3390/biom4030848
Received: 28 March 2014 / Revised: 13 August 2014 / Accepted: 5 September 2014 / Published: 22 September 2014
Cited by 5 | PDF Full-text (4648 KB) | HTML Full-text | XML Full-text
Abstract
Cytoplasmic structures showing a selective concentration of both polyubiquitinated proteins and proteasome have been described in various epithelial, hematopoietic, mesenchymal and neural cells in vitro or in fetal tissues, as well as in chronically-infected, mutated preneoplastic and neoplastic tissues. These cytoplasmic structures differ
[...] Read more.
Cytoplasmic structures showing a selective concentration of both polyubiquitinated proteins and proteasome have been described in various epithelial, hematopoietic, mesenchymal and neural cells in vitro or in fetal tissues, as well as in chronically-infected, mutated preneoplastic and neoplastic tissues. These cytoplasmic structures differ from other ubiquitin-reactive cytoplasmic bodies, like sequestosomes, aggresome-like-induced structures in dendritic cells (DALIS)/non-dendritic cells (ALIS) and aggresomes in showing distinctive ultrastructural organization (particle-rich cytoplasmic structure or PaCS), a cytochemical pattern and a functional profile. Their formation can be induced in vitro in dendritic or natural killer cells by trophic factors and interleukin treatment. They originate in close connection with ribosomes, while, as a result of their growth, the cytoskeleton and other surrounding organelles are usually dislocated outside their core. Interestingly, these particulate cytoplasmic structures are often found to fill cytoplasmic blebs forming proteasome- and polyubiquitinated protein-discharging vesicles, called ectosomes, which are found to detach from the cell and freely float in the extracellular space. To clearly point out the importance of the polyubiquitinated proteins and proteasome containing cytoplasmic structures, their role in cell biology and pathology has been carefully analyzed. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview The 26S Proteasome and Initiation of Gene Transcription
Biomolecules 2014, 4(3), 827-847; doi:10.3390/biom4030827
Received: 14 April 2014 / Revised: 20 August 2014 / Accepted: 1 September 2014 / Published: 10 September 2014
Cited by 10 | PDF Full-text (43928 KB) | HTML Full-text | XML Full-text
Abstract
Transcription activation is the foremost step of gene expression and is modulated by various factors that act in synergy. Misregulation of this process and its associated factors has severe effects and hence requires strong regulatory control. In recent years, growing evidence has highlighted
[...] Read more.
Transcription activation is the foremost step of gene expression and is modulated by various factors that act in synergy. Misregulation of this process and its associated factors has severe effects and hence requires strong regulatory control. In recent years, growing evidence has highlighted the 26S proteasome as an important contributor to the regulation of transcription initiation. Well known for its role in protein destruction, its contribution to protein synthesis was initially viewed with skepticism. However, studies over the past several years have established the proteasome as an important component of transcription initiation through proteolytic and non-proteolytic activities. In this review, we discuss findings made so far in understanding the connections between transcription initiation and the 26S proteasome complex. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation
Biomolecules 2014, 4(3), 774-794; doi:10.3390/biom4030774
Received: 9 May 2014 / Revised: 11 June 2014 / Accepted: 21 July 2014 / Published: 6 August 2014
Cited by 4 | PDF Full-text (3463 KB) | HTML Full-text | XML Full-text
Abstract
Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Figures

Open AccessReview Chaperoning Proteins for Destruction: Diverse Roles of Hsp70 Chaperones and their Co-Chaperones in Targeting Misfolded Proteins to the Proteasome
Biomolecules 2014, 4(3), 704-724; doi:10.3390/biom4030704
Received: 28 March 2014 / Revised: 31 May 2014 / Accepted: 24 June 2014 / Published: 17 July 2014
Cited by 32 | PDF Full-text (2034 KB) | HTML Full-text | XML Full-text
Abstract
Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are
[...] Read more.
Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Protein Quality Control in the Nucleus
Biomolecules 2014, 4(3), 646-661; doi:10.3390/biom4030646
Received: 31 March 2014 / Revised: 20 May 2014 / Accepted: 4 June 2014 / Published: 9 July 2014
Cited by 9 | PDF Full-text (870 KB) | HTML Full-text | XML Full-text
Abstract
In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins
[...] Read more.
In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins are prone to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system. The degradation of misfolded proteins is clearly compartmentalized, so unique degradation pathways exist for misfolded proteins depending on whether their subcellular localization is ER/secretory, mitochondrial, cytosolic or nuclear. Recent studies, mainly in yeast, have shown that the nucleus appears to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Figures

Open AccessReview Modelling Proteasome and Proteasome Regulator Activities
Biomolecules 2014, 4(2), 585-599; doi:10.3390/biom4020585
Received: 25 March 2014 / Revised: 28 May 2014 / Accepted: 30 May 2014 / Published: 20 June 2014
Cited by 4 | PDF Full-text (335 KB) | HTML Full-text | XML Full-text
Abstract
Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have
[...] Read more.
Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a profound impact on immune system function and many cellular metabolic processes. The regulation of proteasome activity involves different mechanisms, such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are invaluable in the analysis; and potentially allow us to predict the complex interactions of proteasome regulatory mechanisms and the final outcomes of the protein degradation rate and MHC class I epitope generation. The pioneering attempts that have been made to mathematically model proteasome activity, cleavage preference variation and their modification by one of the regulatory mechanisms are reviewed here. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview PA28αβ: The Enigmatic Magic Ring of the Proteasome?
Biomolecules 2014, 4(2), 566-584; doi:10.3390/biom4020566
Received: 4 April 2014 / Revised: 15 May 2014 / Accepted: 8 June 2014 / Published: 19 June 2014
Cited by 15 | PDF Full-text (145 KB) | HTML Full-text | XML Full-text
Abstract
PA28αβ is a γ-interferon-induced 11S complex that associates with the ends of the 20S proteasome and stimulates in vitro breakdown of small peptide substrates, but not proteins or ubiquitin-conjugated proteins. In cells, PA28 also exists in larger complexes along with the 19S particle,
[...] Read more.
PA28αβ is a γ-interferon-induced 11S complex that associates with the ends of the 20S proteasome and stimulates in vitro breakdown of small peptide substrates, but not proteins or ubiquitin-conjugated proteins. In cells, PA28 also exists in larger complexes along with the 19S particle, which allows ATP-dependent degradation of proteins; although in vivo a large fraction of PA28 is present as PA28αβ-20S particles whose exact biological functions are largely unknown. Although several lines of evidence strongly indicate that PA28αβ plays a role in MHC class I antigen presentation, the exact molecular mechanisms of this activity are still poorly understood. Herein, we review current knowledge about the biochemical and biological properties of PA28αβ and discuss recent findings concerning its role in modifying the spectrum of proteasome’s peptide products, which are important to better understand the molecular mechanisms and biological consequences of PA28αβ activity. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Back to Top