scholarly journals A SUMO-ubiquitin relay recruits proteasomes to chromosome axes to regulate meiotic recombination

Science ◽  
2017 ◽  
Vol 355 (6323) ◽  
pp. 403-407 ◽  
Author(s):  
H. B. D. Prasada Rao ◽  
Huanyu Qiao ◽  
Shubhang K. Bhatt ◽  
Logan R. J. Bailey ◽  
Hung D. Tran ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Meiotic Prophase ◽  
Meiotic Chromosome ◽  
Ubiquitin Proteasome System ◽  
Protein Stabilization ◽  
E3 Ligases ◽  
Sumo Conjugation ◽  
Ubiquitin Proteasome

Meiosis produces haploid gametes through a succession of chromosomal events, including pairing, synapsis, and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO (small ubiquitin-like modifier)–modification and ubiquitin-proteasome systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpointlike process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.

scholarly journals A SUMO-Ubiquitin Relay Recruits Proteasomes to Chromosome Axes to Regulate Meiotic Recombination

2016 ◽  
Author(s):  
H.B.D. Prasada Rao ◽  
Huanyu Qiao ◽  
Shubhang K. Bhatt ◽  
Logan R.J. Bailey ◽  
Hung D. Tran ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Meiotic Prophase ◽  
Meiotic Chromosome ◽  
Ubiquitin Proteasome System ◽  
Protein Stabilization ◽  
E3 Ligases ◽  
Sumo Modification ◽  
Sumo Conjugation ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

AbstractMeiosis produces haploid gametes through a succession of chromosomal events including pairing, synapsis and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO-modification and ubiquitin-proteasomes systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpoint-like process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.One Sentence SummaryChromosomal events of meiotic prophase in mouse are regulated by proteasome-dependent protein degradation.

scholarly journals Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Megan T. Lewno ◽  
Taixing Cui ◽  
Xuejun Wang
Keyword(s):  
Ubiquitin Proteasome System ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Cop9 Signalosome ◽  
E3 Ligases ◽  
Protein Subunits ◽  
Unique Protein ◽  
Recent Advances ◽  
Regulated Necrosis ◽  
Ubiquitin Proteasome ◽  
Apoptosis And Necrosis

Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

scholarly journals The Ubiquitin Proteasome System in Ischemic and Dilated Cardiomyopathy

2019 ◽  
Vol 20 (24) ◽  
pp. 6354 ◽  
Author(s):  
Sabine Spänig ◽  
Kristina Kellermann ◽  
Maja-Theresa Dieterlen ◽  
Thilo Noack ◽  
Sven Lehmann ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ubiquitin Proteasome System ◽  
Translation Initiation Factor ◽  
Myocardial Tissue ◽  
Activation Markers ◽  
E3 Ligases ◽  
Proteasomal Activity ◽  
Ubiquitin Proteasome ◽  
Statistical Trends ◽  
And Control

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Xiaowei Wu ◽  
Qingyu Luo ◽  
Zhihua Liu
Keyword(s):  
Clinical Practice ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Crucial Role ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Strategies ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Specific Inhibitors

Abstract MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice.

scholarly journals EVI/WLS function is regulated by ubiquitination and linked to ER-associated degradation by ERLIN2

2021 ◽  
Author(s):  
Lucie M. Wolf ◽  
Annika M. Lambert ◽  
Julie Haenlin ◽  
Michael Boutros
Keyword(s):  
Mammalian Cells ◽  
Secretory Pathway ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Wnt Proteins ◽  
Interaction Partners ◽  
Ubiquitin Proteasome ◽  
Endogenous Substrate ◽  
Ubiquitin Conjugating Enzymes ◽  
Ubiquitination Machinery

WNT signalling is important for development in all metazoan animals and is associated with various human diseases. The Ubiquitin-Proteasome System (UPS) and regulatory ER-associated degradation (ERAD) have been implicated in the production of WNT proteins. Here, we investigated how the WNT secretory factor EVI/WLS is ubiquitinated, recognised by ERAD components and subsequently removed from the secretory pathway. We performed a focused, immunoblot-based RNAi screen for factors that influence EVI/WLS protein stability. We identified the VCP-binding proteins FAF2 and UBXN4 as novel interaction partners of EVI/WLS and showed that ERLIN2 links EVI/WLS to the ubiquitination machinery. Interestingly, we found in addition that EVI/WLS is ubiquitinated and degraded in cells irrespective of their level of WNT production. This K11, K48, and K63-linked ubiquitination is mediated by the E2 ubiquitin conjugating enzymes UBE2J2, UBE2K, and UBE2N, but independent of the E3 ligases HRD1/SYVN or GP78/AMFR. Taken together, our study identified factors that link the UPS to the WNT secretory pathway and provides mechanistic details on the fate of an endogenous substrate of regulatory ERAD in mammalian cells.

scholarly journals Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs that Enable Degradation

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5606
Author(s):  
Laura Márquez-Cantudo ◽  
Ana Ramos ◽  
Claire Coderch ◽  
Beatriz de Pascual-Teresa
Keyword(s):  
Cell Cycle ◽  
Hdac Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Protein Targets ◽  
E3 Ligases ◽  
Design And Synthesis ◽  
Ubiquitin Proteasome ◽  
Chromatin Packing ◽  
The Many ◽  
Cycle Regulation

Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.

scholarly journals Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3465
Author(s):  
Ruqaia Abbas ◽  
Sarit Larisch
Keyword(s):  
Apoptotic Cell ◽  
Ubiquitin Proteasome System ◽  
Cancer Therapies ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Positive And Negative Feedback ◽  
Apoptotic Proteins ◽  
The Stability ◽  
Cell Suicide

Apoptosis is a cell suicide process that is essential for development, tissue homeostasis and human health. Impaired apoptosis is associated with a variety of human diseases, including neurodegenerative disorders, autoimmunity and cancer. As the levels of pro- and anti-apoptotic proteins can determine the life or death of cells, tight regulation of these proteins is critical. The ubiquitin proteasome system (UPS) is essential for maintaining protein turnover, which can either trigger or inhibit apoptosis. In this review, we will describe the E3 ligases that regulate the levels of pro- and anti-apoptotic proteins and assisting proteins that regulate the levels of these E3 ligases. We will provide examples of apoptotic cell death modulations using the UPS, determined by positive and negative feedback loop reactions. Specifically, we will review how the stability of p53, Bcl-2 family members and IAPs (Inhibitor of Apoptosis proteins) are regulated upon initiation of apoptosis. As increased levels of oncogenes and decreased levels of tumor suppressor proteins can promote tumorigenesis, targeting these pathways offers opportunities to develop novel anti-cancer therapies, which act by recruiting the UPS for the effective and selective killing of cancer cells.

scholarly journals UbiHub: a data hub for the explorers of ubiquitination pathways

2019 ◽  
Vol 35 (16) ◽  
pp. 2882-2884 ◽  
Author(s):  
Lihua Liu ◽  
David R Damerell ◽  
Leonidas Koukouflis ◽  
Yufeng Tong ◽  
Brian D Marsden ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Phylogenetic Trees ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Protein Target ◽  
Protein Ubiquitination ◽  
Online Resource ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease

Abstract Motivation Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. Results We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. Availability and implementation https://ubihub.thesgc.org.

scholarly journals Keratin 6a reorganization for ubiquitin–proteasomal processing is a direct antimicrobial response

2017 ◽  
Vol 217 (2) ◽  
pp. 731-744 ◽  
Author(s):  
Jonathan K.L. Chan ◽  
Don Yuen ◽  
Priscilla Hiu-Mei Too ◽  
Yan Sun ◽  
Belinda Willard ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Immune Defense ◽  
Antigenic Peptides ◽  
Corneal Epithelial ◽  
E3 Ligases ◽  
Appreciable Increase ◽  
Host Defense Response ◽  
Ubiquitin Proteasome ◽  
Ring E3 Ligases ◽  
Ring E3

Skin and mucosal epithelia deploy antimicrobial peptides (AMPs) to eliminate harmful microbes. We reported that the intermediate filament keratin 6a (K6a) is constitutively processed into antimicrobial fragments in corneal epithelial cells. In this study, we show that K6a network remodeling is a host defense response that directly up-regulates production of keratin-derived AMPs (KAMPs) by the ubiquitin–proteasome system (UPS). Bacterial ligands trigger K6a phosphorylation at S19, S22, S37, and S60, leading to network disassembly. Mutagenic analysis of K6a confirmed that the site-specific phosphorylation augmented its solubility. K6a in the cytosol is ubiquitinated by cullin-RING E3 ligases for subsequent proteasomal processing. Without an appreciable increase in K6a gene expression and proteasome activity, a higher level of cytosolic K6a results in enhanced KAMP production. Although proteasome-mediated proteolysis is known to produce antigenic peptides in adaptive immunity, our findings demonstrate its new role in producing AMPs for innate immune defense. Manipulating K6a phosphorylation or UPS activity may provide opportunities to harness the innate immunity of epithelia against infection.

Sign in / Sign up

Export Citation Format

Share Document