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Ubiquitin System

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 September 2017) | Viewed by 116450

Special Issue Editor

Assoc. Prof. Dr. Nobuhiro Nakamura

E-Mail Website
Guest Editor
Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Interests: transmembrane ubiquitinating and deubiquitinating enzymes; membrane trafficking; mitochondria; mitochondrial dynamics; GPCR signaling; lung immune homeostasis; spermatogenesis

Special Issue Information

Dear Colleagues,

Since the discovery of the ubiquitin-proteasome system, it has been clear that ubiquitin-mediated protein degradation plays pivotal roles in a wide range of cellular processes, including signal transduction, cell growth and differentiation, stress response and immune regulation. More recently, it has become evident that ubiquitination has non-degradative functions in protein trafficking, DNA repair, transcriptional regulation and autophagy. The diverse functions of ubiquitination are controlled by various regulators (e.g., E3 ubiquitin ligases and deubiquitinating enzymes), different architectures of ubiquitin modifications, and ubiquitin recognition mechanisms. Dysfunction of the ubiquitin system often leads to human diseases, such as neurodegenerative diseases and cancer. However, the regulatory mechanism of ubiquitin-mediated cellular processes and the pathogenesis of ubiquitin-related diseases are not fully understood.

In this Special Issue, we will welcome your contributions in the form of original research and review articles in all aspects of “Ubiquitin System”.

Dr. Nobuhiro Nakamura
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • ubiquitin
  • proteasome
  • deubiquitination
  • ubiquitin chain linkage
  • ubiquitin recognition
  • protein degradation
  • protein quality control
  • molecular pathology
  • signal transduction
  • membrane trafficking and dynamics

Published Papers (19 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 223 KiB  
Editorial
Ubiquitin System
by Nobuhiro Nakamura
Int. J. Mol. Sci. 2018, 19(4), 1080; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041080 - 04 Apr 2018
Cited by 43 | Viewed by 7184
Abstract
Ever since the discovery of ubiquitin in 1975[...] Full article
(This article belongs to the Special Issue Ubiquitin System)

Research

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18 pages, 6016 KiB  
Article
Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis
by Masashi Mikamo, Kyoko Kitagawa, Satoshi Sakai, Chiharu Uchida, Tatsuya Ohhata, Koji Nishimoto, Hiroyuki Niida, Sayuri Suzuki, Keiichi I. Nakayama, Naoki Inui, Takafumi Suda and Masatoshi Kitagawa
Int. J. Mol. Sci. 2018, 19(2), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020474 - 06 Feb 2018
Cited by 18 | Viewed by 5403
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF. Full article
(This article belongs to the Special Issue Ubiquitin System)
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3228 KiB  
Article
Lysine-Less Variants of Spinal Muscular Atrophy SMN and SMNΔ7 Proteins Are Degraded by the Proteasome Pathway
by Raúl Sánchez-Lanzas and José G. Castaño
Int. J. Mol. Sci. 2017, 18(12), 2667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122667 - 08 Dec 2017
Cited by 4 | Viewed by 3960
Abstract
Spinal muscular atrophy is due to mutations affecting the SMN1 gene coding for the full-length protein (survival motor neuron; SMN) and the SMN2 gene that preferentially generates an exon 7-deleted protein (SMNΔ7) by alternative splicing. To study SMN and SMNΔ7 degradation in the [...] Read more.
Spinal muscular atrophy is due to mutations affecting the SMN1 gene coding for the full-length protein (survival motor neuron; SMN) and the SMN2 gene that preferentially generates an exon 7-deleted protein (SMNΔ7) by alternative splicing. To study SMN and SMNΔ7 degradation in the cell, we have used tagged versions at the N- (Flag) or C-terminus (V5) of both proteins. Transfection of those constructs into HeLa cells and treatment with cycloheximide showed that those protein constructs were degraded. Proteasomal degradation usually requires prior lysine ubiquitylation. Surprisingly, lysine-less variants of both proteins tagged either at N- (Flag) or C-terminus (V5) were also degraded. The degradation of the endogenous SMN protein, and the protein constructs mentioned above, was mediated by the proteasome, as it was blocked by lactacystin, a specific and irreversible proteasomal inhibitor. The results obtained allowed us to conclude that SMN and SMNΔ7 proteasomal degradation did not absolutely require internal ubiquitylation nor N-terminal ubiquitylation (prevented by N-terminal tagging). While the above conclusions are firmly supported by the experimental data presented, we discuss and justify the need of deep proteomic techniques for the study of SMN complex components (orphan and bound) turn-over to understand the physiological relevant mechanisms of degradation of SMN and SMNΔ7 in the cell. Full article
(This article belongs to the Special Issue Ubiquitin System)
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4456 KiB  
Article
The E3 Ubiquitin Ligase RNF7 Negatively Regulates CARD14/CARMA2sh Signaling
by Gianluca Telesio, Ivan Scudiero, Maddalena Pizzulo, Pellegrino Mazzone, Tiziana Zotti, Serena Voccola, Immacolata Polvere, Pasquale Vito and Romania Stilo
Int. J. Mol. Sci. 2017, 18(12), 2581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122581 - 01 Dec 2017
Cited by 11 | Viewed by 4980
Abstract
The three CARD-containing MAGUK (CARMA) proteins function as scaffolding molecules that regulate activation of the pro-inflammatory transcription factor NF-κB. Recently, mutations in CARMA2 have been linked to psoriasis susceptibility due to their acquired altered capacity to activate NF-κB. By means of two-hybrid screening [...] Read more.
The three CARD-containing MAGUK (CARMA) proteins function as scaffolding molecules that regulate activation of the pro-inflammatory transcription factor NF-κB. Recently, mutations in CARMA2 have been linked to psoriasis susceptibility due to their acquired altered capacity to activate NF-κB. By means of two-hybrid screening with yeast, we identified RING finger protein 7 (RNF7) as an interactor of CARMA2. We present evidence that RNF7 functions as a negative regulator of the NF-κB-activating capacity of CARMA2. Mechanistically, RNF7 influences CARMA2 signaling by regulating the ubiquitination state of MALT1 and the NF-κB-regulatory molecule NEMO. Interestingly, CARMA2short (CARMA2sh) mutants associated with psoriasis susceptibility escape the negative control exerted by RNF7. In conclusion, our findings identify a new mechanism through which the ability of CARMA2 to activate NF-κB is regulated, which could have significant implications for our understanding of why mutations of this protein trigger human psoriasis. Full article
(This article belongs to the Special Issue Ubiquitin System)
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2717 KiB  
Article
The Relevance of the UPS in Fatty Liver Graft Preservation: A New Approach for IGL-1 and HTK Solutions
by Arnau Panisello-Roselló, Eva Verde, Mohamed Amine Zaouali, Marta Flores, Norma Alva, Alexandre Lopez, Emma Folch-Puy, Teresa Carbonell, Georgina Hotter, René Adam and Joan Roselló-Catafau
Int. J. Mol. Sci. 2017, 18(11), 2287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112287 - 31 Oct 2017
Cited by 16 | Viewed by 4968
Abstract
The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold [...] Read more.
The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS. Full article
(This article belongs to the Special Issue Ubiquitin System)
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2011 KiB  
Article
Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart
by Shunichi Yokoe and Michio Asahi
Int. J. Mol. Sci. 2017, 18(11), 2232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112232 - 25 Oct 2017
Cited by 16 | Viewed by 4462
Abstract
The E3 ubiquitin ligase, von Hippel–Lindau (VHL), regulates protein expression by polyubiquitination. Although the protein VHL (pVHL) was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types [...] Read more.
The E3 ubiquitin ligase, von Hippel–Lindau (VHL), regulates protein expression by polyubiquitination. Although the protein VHL (pVHL) was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM) mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN), a potent inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP), a mitochondrial membrane potential (MMP)-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts. Full article
(This article belongs to the Special Issue Ubiquitin System)
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1149 KiB  
Article
Why Ubiquitin Has Not Evolved
by Douglas C. Allan and James C. Phillips
Int. J. Mol. Sci. 2017, 18(9), 1995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18091995 - 16 Sep 2017
Cited by 4 | Viewed by 4373
Abstract
Ubiquitin, discovered less than 50 years ago, tags thousands of diseased proteins for destruction. It is small (only 76 amino acids), and is found unchanged in mammals, birds, fish, and even worms, indicating that ubiquitin is perfect. Key features of its functionality are [...] Read more.
Ubiquitin, discovered less than 50 years ago, tags thousands of diseased proteins for destruction. It is small (only 76 amino acids), and is found unchanged in mammals, birds, fish, and even worms, indicating that ubiquitin is perfect. Key features of its functionality are identified here using critical point thermodynamic scaling theory. These include synchronized pivots and hinges, a stabilizing central pivot, and Fano interference between first- and second-order elements of correlated long-range (allosteric) globular surface shape transitions. Comparison with its closest relative, 76 amino acid Nedd8, shows that the latter lacks all these features. A cracked elastic network model is proposed for the common target shared by many diseased proteins. Full article
(This article belongs to the Special Issue Ubiquitin System)
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2093 KiB  
Article
ρ0 Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids
by André Bordinassi Medina, Marcin Banaszczak, Yang Ni, Ina Aretz and David Meierhofer
Int. J. Mol. Sci. 2017, 18(4), 879; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040879 - 20 Apr 2017
Cited by 4 | Viewed by 5285
Abstract
Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function [...] Read more.
Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function and localization. Previously, we showed that SLC amino acid transporters were on average 6-fold de-ubiquitinated and increased amino acid levels were detected in ρ0 cells (lacking mitochondrial DNA, mtDNA) compared to parental cells. Here, we elucidated the altered functionality of SLC transporters and their dynamic ubiquitination status by measuring the uptake of several isotopically labeled amino acids in both human osteosarcoma 143B.TK- and ρ0 cells. Our pulse chase analysis indicated that de-ubiquitinated amino acid transporters in ρ0 cells were accompanied by an increased transport rate, which leads to higher levels of amino acids in the cell. Finding SLC transport enhancers is an aim of the pharmaceutical industry in order to compensate for loss of function mutations in these genes. Thus, the ubiquitination status of SLC transporters could be an indicator for their functionality, but evidence for a direct connection between de-ubiquitination and transporter activity has to be further elucidated. Full article
(This article belongs to the Special Issue Ubiquitin System)
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13233 KiB  
Article
SAK-HV Decreases the Self-Ubiquitination of MEKK1 to Promote Macrophage Proliferation via MAPK/ERK and JNK Pathways
by Chao Zhang, Yao Chen, Xiangdong Gan, Zhiguang Huang, Minji Zou, Wenliang Fu, Weiwei Xing and Donggang Xu
Int. J. Mol. Sci. 2017, 18(4), 835; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040835 - 19 Apr 2017
Cited by 6 | Viewed by 5539
Abstract
SAK-HV is an anti-atherosclerosis recombinant fusion protein developed by our lab. Our study determined that SAK-HV promoted macrophage proliferation, of which the mechanism was explored by both RAW264.7 cells and primary macrophages. Mass spectrometric analysis and co-immunoprecipitation were combined to screen the SAK-HV-interacting [...] Read more.
SAK-HV is an anti-atherosclerosis recombinant fusion protein developed by our lab. Our study determined that SAK-HV promoted macrophage proliferation, of which the mechanism was explored by both RAW264.7 cells and primary macrophages. Mass spectrometric analysis and co-immunoprecipitation were combined to screen the SAK-HV-interacting proteins in RAW264.7 cells. Confocal microscopy was adopted to detect the localization of SAK-HV in cells. The results indicated that SAK-HV triggered macrophage proliferation via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) pathways by its SAK-mutant functional domain. We screened out Uba1 as the SAK-HV-interacting protein in the RAW264.7 cells and discovered their co-localization in the cytoplasm and nucleus. Inhibiting Uba1 significantly decreased the SAK-HV-induced macrophage proliferation. Thus, we postulated an attractive model of ubiquitination, in which the interactions between Uba1 and specific E2 enzymes are blocked by its interaction with SAK-HV. Based on this model, we detected the decreased self-ubiquitination of MEKK1 after SAK-HV treatment and concluded that SAK-HV inhibits the self-ubiquitination of MEKK1 via its SAK-mutant functional domain to activate MAPK/ERK and JNK pathways, promoting macrophage proliferation. This conclusion highly supported our hypothesized model of ubiquitination at the level of Uba1, which may represent a novel paradigm to promote macrophage proliferation by using the E1 enzyme (Uba1) as a switch. Full article
(This article belongs to the Special Issue Ubiquitin System)
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2758 KiB  
Article
The Effect of Low-Dose Proteasome Inhibition on Pre-Existing Atherosclerosis in LDL Receptor-Deficient Mice
by Nicola Wilck, Mandy Fechner, Cristian Dan, Verena Stangl, Karl Stangl and Antje Ludwig
Int. J. Mol. Sci. 2017, 18(4), 781; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040781 - 07 Apr 2017
Cited by 10 | Viewed by 5591
Abstract
Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose [...] Read more.
Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose proteasome inhibition with bortezomib has been shown to attenuate early atherosclerosis in low-density lipoprotein receptor-deficient (LDLR−/−) mice. The present study investigates the effect of low-dose proteasome inhibition with bortezomib on pre-existing advanced atherosclerosis in LDLR−/− mice. We found that bortezomib treatment of LDLR−/− mice with pre-existing atherosclerosis does not alter lesion burden. Additionally, macrophage infiltration of aortic root plaques, total plasma cholesterol levels, and pro-inflammatory serum markers were not influenced by bortezomib. However, plaques of bortezomib-treated mice exhibited larger necrotic core areas and a significant thinning of the fibrous cap, indicating a more unstable plaque phenotype. Taking recent studies on favorable effects of proteasome inhibition in early atherogenesis into consideration, our data support the hypothesis of stage-dependent effects of proteasome inhibition in atherosclerosis. Full article
(This article belongs to the Special Issue Ubiquitin System)
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Review

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1397 KiB  
Review
Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades
by Fahd Boutouja, Rebecca Brinkmeier, Thomas Mastalski, Fouzi El Magraoui and Harald W. Platta
Int. J. Mol. Sci. 2017, 18(12), 2541; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122541 - 27 Nov 2017
Cited by 42 | Viewed by 7728
Abstract
Autophagy contributes to cellular homeostasis through the degradation of various intracellular targets such as proteins, organelles and microbes. This relates autophagy to various diseases such as infections, neurodegenerative diseases and cancer. A central component of the autophagy machinery is the class III phosphatidylinositol [...] Read more.
Autophagy contributes to cellular homeostasis through the degradation of various intracellular targets such as proteins, organelles and microbes. This relates autophagy to various diseases such as infections, neurodegenerative diseases and cancer. A central component of the autophagy machinery is the class III phosphatidylinositol 3-kinase (PI3K-III) complex, which generates the signaling lipid phosphatidylinositol 3-phosphate (PtdIns3P). The catalytic subunit of this complex is the lipid-kinase VPS34, which associates with the membrane-targeting factor VPS15 as well as the multivalent adaptor protein BECLIN 1. A growing list of regulatory proteins binds to BECLIN 1 and modulates the activity of the PI3K-III complex. Here we discuss the regulation of BECLIN 1 by several different types of ubiquitination, resulting in distinct polyubiquitin chain linkages catalyzed by a set of E3 ligases. This contribution is part of the Special Issue “Ubiquitin System”. Full article
(This article belongs to the Special Issue Ubiquitin System)
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698 KiB  
Review
Regulation of E2F1 Transcription Factor by Ubiquitin Conjugation
by Laurence Dubrez
Int. J. Mol. Sci. 2017, 18(10), 2188; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102188 - 19 Oct 2017
Cited by 21 | Viewed by 9507
Abstract
Ubiquitination is a post-translational modification that defines the cellular fate of intracellular proteins. It can modify their stability, their activity, their subcellular location, and even their interacting pattern. This modification is a reversible event whose implementation is easy and fast. It contributes to [...] Read more.
Ubiquitination is a post-translational modification that defines the cellular fate of intracellular proteins. It can modify their stability, their activity, their subcellular location, and even their interacting pattern. This modification is a reversible event whose implementation is easy and fast. It contributes to the rapid adaptation of the cells to physiological intracellular variations and to intracellular or environmental stresses. E2F1 (E2 promoter binding factor 1) transcription factor is a potent cell cycle regulator. It displays contradictory functions able to regulate both cell proliferation and cell death. Its expression and activity are tightly regulated over the course of the cell cycle progression and in response to genotoxic stress. I discuss here the most recent evidence demonstrating the role of ubiquitination in E2F1’s regulation. Full article
(This article belongs to the Special Issue Ubiquitin System)
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1452 KiB  
Review
G-Protein Dependent Signal Transduction and Ubiquitination in Dictyostelium
by Barbara Pergolizzi, Salvatore Bozzaro and Enrico Bracco
Int. J. Mol. Sci. 2017, 18(10), 2180; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102180 - 19 Oct 2017
Cited by 11 | Viewed by 7532
Abstract
Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions, and it has been widely implicated in human diseases. These receptors activate a common molecular switch that is represented by the heterotrimeric G-protein generating a number of [...] Read more.
Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions, and it has been widely implicated in human diseases. These receptors activate a common molecular switch that is represented by the heterotrimeric G-protein generating a number of second messengers (cAMP, cGMP, DAG, IP3, Ca2+ etc.), leading to a plethora of diverse cellular responses. Spatiotemporal regulation of signals generated by a given GPCR is crucial for proper signalling and is accomplished by a series of biochemical modifications. Over the past few years, it has become evident that many signalling proteins also undergo ubiquitination, a posttranslational modification that typically leads to protein degradation, but also mediates processes such as protein-protein interaction and protein subcellular localization. The social amoeba Dictyostelium discoideum has proven to be an excellent model to investigate signal transduction triggered by GPCR activation, as cAMP signalling via GPCR is a major regulator of chemotaxis, cell differentiation, and multicellular morphogenesis. Ubiquitin ligases have been recently involved in these processes. In the present review, we will summarize the most significant pathways activated upon GPCRs stimulation and discuss the role played by ubiquitination in Dictyostelium cells. Full article
(This article belongs to the Special Issue Ubiquitin System)
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650 KiB  
Review
Ubiquitination in Periodontal Disease: A Review
by Sachio Tsuchida, Mamoru Satoh, Masaki Takiwaki and Fumio Nomura
Int. J. Mol. Sci. 2017, 18(7), 1476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18071476 - 10 Jul 2017
Cited by 28 | Viewed by 6248
Abstract
Periodontal disease (periodontitis) is a chronic inflammatory condition initiated by microbial infection that leads to gingival tissue destruction and alveolar bone resorption. The periodontal tissue’s response to dental plaque is characterized by the accumulation of polymorphonuclear leukocytes, macrophages, and lymphocytes, all of which [...] Read more.
Periodontal disease (periodontitis) is a chronic inflammatory condition initiated by microbial infection that leads to gingival tissue destruction and alveolar bone resorption. The periodontal tissue’s response to dental plaque is characterized by the accumulation of polymorphonuclear leukocytes, macrophages, and lymphocytes, all of which release inflammatory mediators and cytokines to orchestrate the immunopathogenesis of periodontal disease. Ubiquitination is achieved by a mechanism that involves a number of factors, including an ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin–protein ligase. Ubiquitination is a post-translational modification restricted to eukaryotes that are involved in essential host processes. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Increasing numbers of recent reports have provided evidence that many approaches are delivering promising reports for discovering the relationship between ubiquitination and periodontal disease. The scope of this review was to investigate recent progress in the discovery of ubiquitinated protein in diseased periodontium and to discuss the ubiquitination process in periodontal diseases. Full article
(This article belongs to the Special Issue Ubiquitin System)
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533 KiB  
Review
Biological and Physicochemical Functions of Ubiquitylation Revealed by Synthetic Chemistry Approaches
by Daichi Morimoto, Erik Walinda, Kenji Sugase and Masahiro Shirakawa
Int. J. Mol. Sci. 2017, 18(6), 1145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18061145 - 27 May 2017
Cited by 4 | Viewed by 5293
Abstract
Most intracellular proteins are subjected to post-translational modification by ubiquitin. Accordingly, it is of fundamental importance to investigate the biological and physicochemical effects of ubiquitylation on substrate proteins. However, preparation of ubiquitylated proteins by an enzymatic synthesis bears limitations in terms of yield [...] Read more.
Most intracellular proteins are subjected to post-translational modification by ubiquitin. Accordingly, it is of fundamental importance to investigate the biological and physicochemical effects of ubiquitylation on substrate proteins. However, preparation of ubiquitylated proteins by an enzymatic synthesis bears limitations in terms of yield and site-specificity. Recently established chemical ubiquitylation methodologies can overcome these problems and provide a new understanding of ubiquitylation. Herein we describe the recent chemical ubiquitylation procedures with a focus on the effects of ubiquitylation on target proteins revealed by the synthetic approach. Full article
(This article belongs to the Special Issue Ubiquitin System)
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873 KiB  
Review
Regulation of Ubiquitin Enzymes in the TGF-β Pathway
by Prasanna Vasudevan Iyengar
Int. J. Mol. Sci. 2017, 18(4), 877; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040877 - 20 Apr 2017
Cited by 33 | Viewed by 6652
Abstract
The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to [...] Read more.
The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to dysregulate the pathway causing diseases such as bone disorders, cancer and metastasis. These enzymes and their counterparts are increasingly being tested as druggable targets, and thus a deeper understanding of the enzymes is required. This review summarizes the roles of specific ubiquitin modifying enzymes in the TGF-β pathway and how they are regulated. Full article
(This article belongs to the Special Issue Ubiquitin System)
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984 KiB  
Review
A Review on Ubiquitination of Neurotrophin Receptors: Facts and Perspectives
by Julia Sánchez-Sánchez and Juan Carlos Arévalo
Int. J. Mol. Sci. 2017, 18(3), 630; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18030630 - 14 Mar 2017
Cited by 14 | Viewed by 7159
Abstract
Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) have been studied recently. TrkA is the most studied receptor in terms of its [...] Read more.
Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination. Additional studies are needed that focus on the ubiquitination of TrkB, TrkC, and p75NTR in order to further understand the role of ubiquitination in their physiological and pathological functions. Here we review what is currently known regarding the ubiquitination of neurotrophin receptors and its physiological and pathological relevance. Full article
(This article belongs to the Special Issue Ubiquitin System)
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Review
The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases
by Chon-Kit Chou, Yu-Ting Chang, Michal Korinek, Yei-Tsung Chen, Ya-Ting Yang, Steve Leu, I-Ling Lin, Chin-Ju Tang and Chien-Chih Chiu
Int. J. Mol. Sci. 2017, 18(3), 483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18030483 - 24 Feb 2017
Cited by 41 | Viewed by 9111 | Correction
Abstract
Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two [...] Read more.
Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-β receptor-signaling pathways by deubiquitinating the TGF-β receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-β target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson’s disease, virus infection, and cancer-related signaling networks. Full article
(This article belongs to the Special Issue Ubiquitin System)
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Case Report
High Levels of Serum Ubiquitin and Proteasome in a Case of HLA-B27 Uveitis
by Settimio Rossi, Carlo Gesualdo, Rosa Maisto, Maria Consiglia Trotta, Nadia Di Carluccio, Annalisa Brigida, Valentina Di Iorio, Francesco Testa, Francesca Simonelli, Michele D’Amico and Clara Di Filippo
Int. J. Mol. Sci. 2017, 18(3), 505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18030505 - 26 Feb 2017
Cited by 2 | Viewed by 4259
Abstract
In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came [...] Read more.
In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day) for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1) and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized. Full article
(This article belongs to the Special Issue Ubiquitin System)
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