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The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes

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

Deadline for manuscript submissions: closed (16 June 2019) | Viewed by 57953

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Prof. Tommer Ravid

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Department of Biological Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel
Interests: ubiquitin-proteasome system; protein quality control; ERAD; yeast genetics & proteomics
Special Issues, Collections and Topics in MDPI journals

Prof. Michael Glickman

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Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel

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Dear Colleagues,

“Zomes” in their biological context are large cellular complexes, many of which relate to the ubiquitin-proteasome system for maintaining proteostasis. The biannual “Zomes” conference series was initiated in 1999 as a grassroots initiative of scientists studying three related protein complexes—the 26S proteasome, the COP9 signalosome, and the translation initiation factor eIF3, altogether termed PCI. Since then, each “Zomes” conference had its own thematic focus, which reflected the current state of the field.

In 2014, we issued a Special Issue of Biomolecules that focused on “Proteasomes and Its Regulators”, and it still attracts the attention of many researchers in the field to date. We now wish to expand this initiative by asking respective participants of the tenth “Zomes” meeting, which highlights the broader cellular impact of PCI complexes, to contribute to this follow-up Special Issue. This can be done by submitting reviews, new methods, and original articles covering many aspects of the function of PCI complexes. These include, but are not limited to, the structure, mechanisms, and roles of PCI; regulation of PCI function; PCI and protein quality control: protein degradation, misfolding, and aggregation; and PCI in health and disease. By bringing together the current state-of-the-art in “PCI” research, we aim to emphasize the importance of crosstalk between different research fields with similar structural organization and regulatory mechanisms.

Prof. Tommer Ravid
Prof. Michael Glickman
Guest Editors

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Keywords

26S proteasome
COP9 signalosome
translation initiation factor eIF3
ubiquitin-proteasome system
cellular regulation

Published Papers (12 papers)

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Research

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14 pages, 1549 KiB

Open AccessArticle

Remodeling Membrane Binding by Mono-Ubiquitylation

by Neta Tanner, Oded Kleifeld, Iftach Nachman and Gali Prag

Biomolecules 2019, 9(8), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080325 - 31 Jul 2019

Cited by 6 | Viewed by 2850

Abstract

Ubiquitin (Ub) receptors respond to ubiquitylation signals. They bind ubiquitylated substrates and exert their activity in situ. Intriguingly, Ub receptors themselves undergo rapid ubiquitylation and deubiquitylation. Here we asked what is the function of ubiquitylation of Ub receptors? We focused on yeast epsin, a Ub receptor that decodes the ubiquitylation signal of plasma membrane proteins into an endocytosis response. Using mass spectrometry, we identified lysine-3 as the major ubiquitylation site in the epsin plasma membrane binding domain. By projecting this ubiquitylation site onto our crystal structure, we hypothesized that this modification would compete with phosphatidylinositol-4,5-bisphosphate (PIP₂) binding and dissociate epsin from the membrane. Using an E. coli-based expression of an authentic ubiquitylation apparatus, we purified ubiquitylated epsin. We demonstrated in vitro that in contrast to apo epsin, the ubiquitylated epsin does not bind to either immobilized PIPs or PIP₂-enriched liposomes. To test this hypothesis in vivo, we mimicked ubiquitylation by the fusion of Ub at the ubiquitylation site. Live cell imaging demonstrated that the mimicked ubiquitylated epsin dissociates from the membrane. Our findings suggest that ubiquitylation of the Ub receptors dissociates them from their products to allow binding to a new ubiquitylated substrates, consequently promoting cyclic activity of the Ub receptors. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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32 pages, 4458 KiB

Open AccessArticle

COP9 Signalosome Interaction with UspA/Usp15 Deubiquitinase Controls VeA-Mediated Fungal Multicellular Development

by Cindy Meister, Karl G. Thieme, Sabine Thieme, Anna M. Köhler, Kerstin Schmitt, Oliver Valerius and Gerhard H. Braus

Biomolecules 2019, 9(6), 238; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060238 - 18 Jun 2019

Cited by 15 | Viewed by 4553

Abstract

COP9 signalosome (CSN) and Den1/A deneddylases physically interact and promote multicellular development in fungi. CSN recognizes Skp1/cullin-1/Fbx E3 cullin-RING ligases (CRLs) without substrate and removes their posttranslational Nedd8 modification from the cullin scaffold. This results in CRL complex disassembly and allows Skp1 adaptor/Fbx receptor exchange for altered substrate specificity. We characterized the novel ubiquitin-specific protease UspA of the mold Aspergillus nidulans, which corresponds to CSN-associated human Usp15 and interacts with six CSN subunits. UspA reduces amounts of ubiquitinated proteins during fungal development, and the uspA gene expression is repressed by an intact CSN. UspA is localized in proximity to nuclei and recruits proteins related to nuclear transport and transcriptional processing, suggesting functions in nuclear entry control. UspA accelerates the formation of asexual conidiospores, sexual development, and supports the repression of secondary metabolite clusters as the derivative of benzaldehyde (dba) genes. UspA reduces protein levels of the fungal NF-kappa B-like velvet domain protein VeA, which coordinates differentiation and secondary metabolism. VeA stability depends on the Fbx23 receptor, which is required for light controlled development. Our data suggest that the interplay between CSN deneddylase, UspA deubiquitinase, and SCF-Fbx23 ensures accurate levels of VeA to support fungal development and an appropriate secondary metabolism. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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15 pages, 4556 KiB

Open AccessArticle

In-depth Analysis of the Lid Subunits Assembly Mechanism in Mammals

by Minghui Bai, Xian Zhao, Kazutaka Sahara, Yuki Ohte, Yuko Hirano, Takeumi Kaneko, Hideki Yashiroda and Shigeo Murata

Biomolecules 2019, 9(6), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060213 - 31 May 2019

Cited by 10 | Viewed by 3007

Abstract

The 26S proteasome is a key player in the degradation of ubiquitinated proteins, comprising a 20S core particle (CP) and a 19S regulatory particle (RP). The RP is further divided into base and lid subcomplexes, which are assembled independently from each other. We have previously demonstrated the assembly pathway of the CP and the base by observing assembly intermediates resulting from knockdowns of each proteasome subunit and the assembly chaperones. In this study, we examine the assembly pathway of the mammalian lid, which remains to be elucidated. We show that the lid assembly pathway is conserved between humans and yeast. The final step is the incorporation of Rpn12 into the assembly intermediate consisting of two modular complexes, Rpn3-7-15 and Rpn5-6-8-9-11, in both humans and yeast. Furthermore, we dissect the assembly pathways of the two modular complexes by the knockdown of each lid subunit. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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18 pages, 2036 KiB

Open AccessArticle

Effect of Protein Denaturation and Enzyme Inhibitors on Proteasomal-Mediated Production of Peptides in Human Embryonic Kidney Cells

by Sayani Dasgupta, Michael A. Fishman, Leandro M. Castro, Alexandre K. Tashima, Emer S. Ferro and Lloyd D. Fricker

Biomolecules 2019, 9(6), 207; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060207 - 28 May 2019

Cited by 9 | Viewed by 3818

Abstract

Peptides produced by the proteasome have been proposed to function as signaling molecules that regulate a number of biological processes. In the current study, we used quantitative peptidomics to test whether conditions that affect protein stability, synthesis, or turnover cause changes in the levels of peptides in Human Embryonic Kidney 293T (HEK293T) cells. Mild heat shock (42 °C for 1 h) or treatment with the deubiquitinase inhibitor b-AP15 led to higher levels of ubiquitinated proteins but did not significantly increase the levels of intracellular peptides. Treatment with cycloheximide, an inhibitor of protein translation, did not substantially alter the levels of intracellular peptides identified herein. Cells treated with a combination of epoxomicin and bortezomib showed large increases in the levels of most peptides, relative to the levels in cells treated with either compound alone. Taken together with previous studies, these results support a mechanism in which the proteasome cleaves proteins into peptides that are readily detected in our assays (i.e., 6–37 amino acids) and then further degrades many of these peptides into smaller fragments. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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Review

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14 pages, 1243 KiB

Open AccessReview

How the 26S Proteasome Degrades Ubiquitinated Proteins in the Cell

by Bernat Coll-Martínez and Bernat Crosas

Biomolecules 2019, 9(9), 395; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090395 - 22 Aug 2019

Cited by 16 | Viewed by 4188

Abstract

The 26S proteasome is the central element of proteostasis regulation in eukaryotic cells, it is required for the degradation of protein factors in multiple cellular pathways and it plays a fundamental role in cell stability. The main aspects of proteasome mediated protein degradation have been highly (but not totally) described during three decades of intense cellular, molecular, structural and chemical biology research and tool development. Contributions accumulated within this time lapse allow researchers today to go beyond classical partial views of the pathway, and start generating almost complete views of how the proteasome acts inside the cell. These views have been recently reinforced by cryo-electron microscopy and mechanistic works that provide from landscapes of proteasomal populations distributed in distinct intracellular contexts, to detailed shots of each step of the process of degradation of a given substrate, of the factors that regulate it, and precise measurements of the speed of degradation. Here, we present an updated digest of the most recent developments that significantly contribute in our understanding of how the 26S proteasome degrades hundreds of ubiquitinated substrates in multiple intracellular environments. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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13 pages, 1202 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hunt for Degrons of the 26S Proteasome

by Hadar Ella, Yuval Reiss and Tommer Ravid

Biomolecules 2019, 9(6), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060230 - 13 Jun 2019

Cited by 18 | Viewed by 5735

Abstract

Since the discovery of ubiquitin conjugation as a cellular mechanism that triggers proteasomal degradation, the mode of substrate recognition by the ubiquitin-ligation system has been the holy grail of research in the field. This entails the discovery of recognition determinants within protein substrates, which are part of a degron, and explicit E3 ubiquitin (Ub)-protein ligases that trigger their degradation. Indeed, many protein substrates and their cognate E3′s have been discovered in the past 40 years. In the course of these studies, various degrons have been randomly identified, most of which are acquired through post-translational modification, typically, but not exclusively, protein phosphorylation. Nevertheless, acquired degrons cannot account for the vast diversity in cellular protein half-life times. Obviously, regulation of the proteome is largely determined by inherent degrons, that is, determinants integral to the protein structure. Inherent degrons are difficult to predict since they consist of diverse sequence and secondary structure features. Therefore, unbiased methods have been employed for their discovery. This review describes the history of degron discovery methods, including the development of high throughput screening methods, state of the art data acquisition and data analysis. Additionally, it summarizes major discoveries that led to the identification of cognate E3 ligases and hitherto unrecognized complexities of degron function. Finally, we discuss future perspectives and what still needs to be accomplished towards achieving the goal of understanding how the eukaryotic proteome is regulated via coordinated action of components of the ubiquitin-proteasome system. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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10 pages, 418 KiB

Open AccessReview

Role of Cop9 Signalosome Subunits in the Environmental and Hormonal Balance of Plant

by Amit Kumar Singh and Daniel A. Chamovitz

Biomolecules 2019, 9(6), 224; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060224 - 09 Jun 2019

Cited by 21 | Viewed by 4256

Abstract

The COP9 (Constitutive photomorphogenesis 9) signalosome (CSN) is a highly conserved protein complex that influences several signaling and developmental processes. The COP9 signalosome consists of eight subunits, among which two subunits, CSN5 and CSN6, contain an Mpr1/Pad1 N-terminal (MPN) domain and the remaining six subunits contain a proteasome, COP9 signalosome, and initiation factor 3 (PCI) domain. In plants, each MPN subunit is encoded by two genes, which is not the case in other organisms. This review aims to provide in-depth knowledge of each COP9 signalosome subunit, concentrating on genetic analysis of both partial and complete loss-of-function mutants. At the beginning of this review, the role of COP9 signalosome in the hormonal signaling and defense is discussed, whereas later sections deal in detail with the available partial loss-of-function, hypomorphic mutants of each subunit. All available hypomorphic mutants are compared based on their growth response and deneddylation activity. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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28 pages, 1180 KiB

Open AccessReview

Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

by Jelena Milic, Yuan Tian and Jürgen Bernhagen

Biomolecules 2019, 9(6), 217; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060217 - 05 Jun 2019

Cited by 21 | Viewed by 4819

Abstract

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-κB signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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16 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

The Contribution of the 20S Proteasome to Proteostasis

by Fanindra Kumar Deshmukh, Dana Yaffe, Maya A. Olshina, Gili Ben-Nissan and Michal Sharon

Biomolecules 2019, 9(5), 190; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9050190 - 16 May 2019

Cited by 90 | Viewed by 11433

Abstract

The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation—no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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28 pages, 1636 KiB

Open AccessReview

Intracellular Peptides in Cell Biology and Pharmacology

by Christiane B. de Araujo, Andrea S. Heimann, Ricardo A. Remer, Lilian C. Russo, Alison Colquhoun, Fábio L. Forti and Emer S. Ferro

Biomolecules 2019, 9(4), 150; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9040150 - 16 Apr 2019

Cited by 37 | Viewed by 5766

Abstract

Intracellular peptides are produced by proteasomes following degradation of nuclear, cytosolic, and mitochondrial proteins, and can be further processed by additional peptidases generating a larger pool of peptides within cells. Thousands of intracellular peptides have been sequenced in plants, yeast, zebrafish, rodents, and in human cells and tissues. Relative levels of intracellular peptides undergo changes in human diseases and also when cells are stimulated, corroborating their biological function. However, only a few intracellular peptides have been pharmacologically characterized and their biological significance and mechanism of action remains elusive. Here, some historical and general aspects on intracellular peptides’ biology and pharmacology are presented. Hemopressin and Pep19 are examples of intracellular peptides pharmacologically characterized as inverse agonists to cannabinoid type 1 G-protein coupled receptors (CB1R), and hemopressin fragment NFKF is shown herein to attenuate the symptoms of pilocarpine-induced epileptic seizures. Intracellular peptides EL28 (derived from proteasome 26S protease regulatory subunit 4; Rpt2), PepH (derived from Histone H2B type 1-H), and Pep5 (derived from G1/S-specific cyclin D2) are examples of peptides that function intracellularly. Intracellular peptides are suggested as biological functional molecules, and are also promising prototypes for new drug development. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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17 pages, 2418 KiB

Open AccessBrief Report

The Proteasome Lid Triggers COP9 Signalosome Activity during the Transition of Saccharomyces cerevisiae Cells into Quiescence

by Laylan Bramasole, Abhishek Sinha, Dana Harshuk, Angela Cirigliano, Gurevich Sylvia, Zanlin Yu, Rinat Lift Carmeli, Michael H. Glickman, Teresa Rinaldi and Elah Pick

Biomolecules 2019, 9(9), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090449 - 04 Sep 2019

Cited by 5 | Viewed by 2942

Abstract

The class of Cullin–RING E3 ligases (CRLs) selectively ubiquitinate a large portion of proteins targeted for proteolysis by the 26S proteasome. Before degradation, ubiquitin molecules are removed from their conjugated proteins by deubiquitinating enzymes, a handful of which are associated with the proteasome. The CRL activity is triggered by modification of the Cullin subunit with the ubiquitin-like protein, NEDD8 (also known as Rub1 in Saccharomyces cerevisiae). Cullin modification is then reversed by hydrolytic action of the COP9 signalosome (CSN). As the NEDD8–Rub1 catalytic cycle is not essential for the viability of S. cerevisiae, this organism is a useful model system to study the alteration of Rub1–CRL conjugation patterns. In this study, we describe two distinct mutants of Rpn11, a proteasome-associated deubiquitinating enzyme, both of which exhibit a biochemical phenotype characterized by high accumulation of Rub1-modified Cdc53–Cullin1 (yCul1) upon entry into quiescence in S. cerevisiae. Further characterization revealed proteasome 19S-lid-associated deubiquitination activity that authorizes the hydrolysis of Rub1 from yCul1 by the CSN complex. Thus, our results suggest a negative feedback mechanism via proteasome capacity on upstream ubiquitinating enzymes. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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11 pages, 1245 KiB

Open AccessPerspective

Are Inositol Polyphosphates the Missing Link in Dynamic Cullin RING Ligase Regulation by the COP9 Signalosome?

by Xiaozhe Zhang and Feng Rao

Biomolecules 2019, 9(8), 349; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080349 - 07 Aug 2019

Cited by 9 | Viewed by 3713

Abstract

The E3 ligase activity of Cullin RING Ligases (CRLs) is controlled by cycles of neddylation/deneddylation and intimately regulated by the deneddylase COP9 Signalosome (CSN), one of the proteasome lid-CSN-initiation factor 3 (PCI) domain-containing “Zomes” complex. Besides catalyzing the removal of stimulatory Cullin neddylation, CSN also provides a docking platform for other proteins that might play a role in regulating CRLs, notably protein kinases and deubiquitinases. During the CRL activity cycle, CRL–CSN complexes are dynamically assembled and disassembled. Mechanisms underlying complex dynamics remain incompletely understood. Recently, the inositol polyphosphate metabolites (IP6, IP7) and their metabolic enzymes (IP5K, IP6K) have been discovered to participate in CRL–CSN complex formation as well as stimulus-dependent dissociation. Here we discuss these mechanistic insights in light of recent advances in elucidating structural basis of CRL–CSN complexes. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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