scholarly journals The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 7936
Author(s):  
Jordan Blondelle ◽  
Andrea Biju ◽  
Stephan Lange
Keyword(s):  
Muscle Development ◽  
Cell Function ◽  
Striated Muscle ◽  
Muscle Protein ◽  
Ubiquitin Proteasome System ◽  
Striated Muscles ◽  
E3 Ligases ◽  
Protein Substrates ◽  
Ubiquitin Proteasome ◽  
Ring E3 Ligases

The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin–proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and crucial roles in cross striated muscles than previously anticipated. This review highlights some of the findings on the multifaceted functions of cullin-RING E3-ligases, their substrate adapters, muscle protein substrates, and regulatory proteins, such as the Cop9 signalosome, for the development of cross striated muscles, and their roles in the etiology of myopathies.

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.

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.

Caenorhabditis elegans twist plays an essential role in non-striated muscle development

Development ◽  
2000 ◽  
Vol 127 (10) ◽  
pp. 2041-2051 ◽  
Author(s):  
A.K. Corsi ◽  
S.A. Kostas ◽  
A. Fire ◽  
M. Krause
Keyword(s):  
Caenorhabditis Elegans ◽  
Essential Role ◽  
Muscle Development ◽  
Target Genes ◽  
Striated Muscle ◽  
Egg Laying ◽  
Bhlh Transcription Factor ◽  
Striated Muscles ◽  
Downstream Target ◽  
Mesodermal Development

The basic helix-loop-helix (bHLH) transcription factor Twist plays a role in mesodermal development in both invertebrates and vertebrates. In an effort to understand the role of the unique Caenorhabditis elegans Twist homolog, hlh-8, we analyzed mesodermal development in animals with a deletion in the hlh-8 locus. This deletion was predicted to represent a null allele because the HLH domain is missing and the reading frame for the protein is disrupted. Animals lacking CeTwist function were constipated and egg-laying defective. Both of these defects were rescued in transgenic mutant animals expressing wild-type hlh-8. Observing a series of mesoderm-specific markers allowed us to characterize the loss of hlh-8 function more thoroughly. Our results demonstrate that CeTwist performs an essential role in the proper development of a subset of mesodermal tissues in C. elegans. We found that CeTwist was required for the formation of three out of the four non-striated enteric muscles born in the embryo. In contrast, CeTwist was not required for the formation of the embryonically derived striated muscles. Most of the post-embryonic mesoderm develops from a single lineage. CeTwist was necessary for appropriate patterning in this lineage and was required for expression of two downstream target genes, but was not required for the expression of myosin, a marker of differentiation. Our results suggest that mesodermal patterning by Twist is an evolutionarily conserved function.

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 Excessive glucocorticoid-induced muscle MuRF1 overexpression is independent of Akt/FoXO1 pathway

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Xiao Juan Wang ◽  
Jing Jing Xiao ◽  
Lei Liu ◽  
Hong Chao Jiao ◽  
Hai Lin
Keyword(s):  
Muscle Protein ◽  
Mammalian Target Of Rapamycin ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
C2c12 Cells ◽  
Detectable Effect ◽  
High Concentration ◽  
Mtor Phosphorylation ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS)-dependent proteolysis plays a major role in the muscle catabolic action of glucocorticoids (GCs). Atrogin-1 and muscle-specific RING finger protein 1 (MuRF1), two E3 ubiquitin ligases, are uniquely expressed in muscle. It has been previously demonstrated that GC treatment induced MuRF1 and atrogin-1 overexpression. However, it is yet unclear whether the higher pharmacological dose of GCs induced muscle protein catabolism through MuRF1 and atrogin-1. In the present study, the role of atrogin-1 and MuRF1 in C2C12 cells protein metabolism during excessive dexamethasone (DEX) was studied. The involvement of Akt/forkhead box O1 (FoXO1) signaling pathway and the cross-talk between anabolic regulator mammalian target of rapamycin (mTOR) and catabolic regulator FoXO1 were investigated. High concentration of DEX increased MuRF1 protein level in a time-dependent fashion (P<0.05), while had no detectable effect on atrogin-1 protein (P>0.05). FoXO1/3a (Thr24/32) phosphorylation was enhanced (P<0.05), mTOR phosphorylation was suppressed (P<0.05), while Akt protein expression was not affected (P>0.05) by DEX. RU486 treatment inhibited the DEX-induced increase of FoXO1/3a phosphorylation (P<0.05) and MuRF1 protein; LY294002 (LY) did not restore the stimulative effect of DEX on the FoXO1/3a phosphorylation (P>0.05), but inhibited the activation of MuRF1 protein induced by DEX (P<0.05); rapamycin (RAPA) inhibited the stimulative effect of DEX on the FoXO1/3a phosphorylation and MuRF1 protein (P<0.05).

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.

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