scholarly journals Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

2020 ◽  
Vol 21 (17) ◽  
pp. 5962 ◽  
Author(s):  
Takashi Shiromizu ◽  
Mizuki Yuge ◽  
Kousuke Kasahara ◽  
Daishi Yamakawa ◽  
Takaaki Matsui ◽  
...  
Keyword(s):  
Essential Role ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
E3 Ubiquitin Ligases ◽  
Complex Disorders ◽  
Ciliary Function ◽  
Ubiquitin Proteasome ◽  
And Function

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin–proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders.

scholarly journals New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases

2014 ◽  
Vol 42 (1) ◽  
pp. 103-107 ◽  
Author(s):  
Peter Canning ◽  
Alex N. Bullock
Keyword(s):  
Drug Targets ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
E3 Ligases ◽  
Btb Domain ◽  
C Terminus ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
And Function

E3 ubiquitin ligases that direct substrate proteins to the ubiquitin–proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin–RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-à-brac) proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB–BACK (BTB and C-terminal Kelch)–Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer's disease and Parkinson's disease. Structural characterization of BTB–Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical ‘3-box’ at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways.

scholarly journals Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1327
Author(s):  
Stefanie Haberecht-Müller ◽  
Elke Krüger ◽  
Jens Fielitz
Keyword(s):  
Protein Degradation ◽  
Muscle Atrophy ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Regulation Of Activity ◽  
Ubiquitin Proteasome ◽  
And Function

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.

scholarly journals Tearin' Up My Heart: Proteolysis in the Cardiac Sarcomere

2011 ◽  
Vol 286 (12) ◽  
pp. 9929-9934 ◽  
Author(s):  
Andrea L. Portbury ◽  
Monte S. Willis ◽  
Cam Patterson
Keyword(s):  
Cardiovascular Health ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
Cardiac Sarcomere ◽  
Ubiquitin Proteasome ◽  
Health And Disease ◽  
The Individual ◽  
And Function ◽  
Calpain System

Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system-mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere.

scholarly journals Essential Role of Septin 7 in Skeletal Muscle Structure and Function

2020 ◽  
Vol 118 (3) ◽  
pp. 258a
Author(s):  
Laszlo Csernoch ◽  
Mónika Gönczi ◽  
Zsolt Ráduly ◽  
László Szabó ◽  
Nóra Dobrosi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Essential Role ◽  
Structure And Function ◽  
Muscle Structure ◽  
And Function

scholarly journals Essential Role of Ubiquitin-Proteasome System in Normal Regulation of Insulin Secretion

2006 ◽  
Vol 281 (19) ◽  
pp. 13015-13020 ◽  
Author(s):  
Miho Kawaguchi ◽  
Kohtaro Minami ◽  
Kazuaki Nagashima ◽  
Susumu Seino
Keyword(s):  
Insulin Secretion ◽  
Essential Role ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

Understanding the relationship between the microbiome and the structure and function of the pig gastrointestinal tract

2022 ◽  
pp. 165-178
Author(s):  
Chunlong Mu ◽  
◽  
Weiyun Zhu ◽  
Keyword(s):  
Gut Microbiome ◽  
Amino Acid Metabolism ◽  
Essential Role ◽  
Short Chain Fatty Acids ◽  
Structure And Function ◽  
Host Interaction ◽  
Epithelial Structure ◽  
And Function ◽  
The Relationship

The gut epithelium acts as a barrier to the gut environment. The integrity of the epithelial structure and function is thus critical for microbiome-host interaction. The gut microbiome can regulate the utilization and synthesis of mucin, the expressions of the intercellular junction complex, and the functioning of specific epithelial cells, such as enterochromaffin cells and stem cells in pigs. The factors involved include microbial metabolites, especially short-chain fatty acids and host-microbe co-metabolism. Recent studies have revealed the essential role of amino acid metabolism in regulating the gut microbiome and epithelial barrier. This chapter discusses how the pig gut microbiome modulates epithelial structure and function, highlighting findings that reflect the relationship between the gut microbiome, intestinal structure and function.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5938
Author(s):  
Jeongkwan Hong ◽  
Minho Won ◽  
Hyunju Ro
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Intercellular Signaling ◽  
Cellular Functions ◽  
Ring Type ◽  
Ubiquitin Ligase Activity ◽  
Ubiquitin Proteasome

The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression.

scholarly journals Targeting Cullin–RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

2015 ◽  
Vol 467 (3) ◽  
pp. 365-386 ◽  
Author(s):  
Emil Bulatov ◽  
Alessio Ciulli
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
Structure Assembly

In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

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