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 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.

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 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 Targeting the Ubiquitin System in Glioblastoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Nico Scholz ◽  
Kathreena M. Kurian ◽  
Florian A. Siebzehnrubl ◽  
Julien D. F. Licchesi
Keyword(s):  
Drug Targets ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Primary Brain Tumor ◽  
E3 Ubiquitin Ligases ◽  
Deubiquitinating Enzymes ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies ◽  
Promising Source

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

scholarly journals E3 Ubiquitin Ligase-Mediated Regulation of Osteoblast Differentiation and Bone Formation

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianlin Shen ◽  
Bowen Fu ◽  
Yanfang Li ◽  
Yanjiao Wu ◽  
Hongxun Sang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Deep Understanding ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Moiety ◽  
Regulatory Effects ◽  
And Function

The ubiquitin–proteasome system (UPS) is an essential pathway that regulates the homeostasis and function of intracellular proteins and is a crucial protein-degradation system in osteoblast differentiation and bone formation. Abnormal regulation of ubiquitination leads to osteoblast differentiation disorders, interfering with bone formation and ultimately leading to osteoporosis. E3 ubiquitin ligases (E3) promote addition of a ubiquitin moiety to substrate proteins, specifically recognizing the substrate and modulating tyrosine kinase receptors, signaling proteins, and transcription factors involved in the regulation of osteoblast proliferation, differentiation, survival, and bone formation. In this review, we summarize current progress in the understanding of the function and regulatory effects of E3 ligases on the transcription factors and signaling pathways that regulate osteoblast differentiation and bone formation. A deep understanding of E3 ligase-mediated regulation of osteoblast differentiation provides a scientific rationale for the discovery and development of novel E3-targeting therapeutic strategies for osteoporosis.

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 The Roles of the Ubiquitin–Proteasome System in the Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1526
Author(s):  
Junyan Qu ◽  
Tingting Zou ◽  
Zhenghong Lin
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Defense Mechanism ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Endoplasmic Reticulum Stress Pathway

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress.

scholarly journals Inhibitor of apoptosis proteins as E3 ligases for ubiquitin and NEDD8

2013 ◽  
Vol 4 (2) ◽  
pp. 161-171 ◽  
Author(s):  
Shinji Kamada
Keyword(s):  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Ubiquitin E3 Ligase ◽  
The Family ◽  
Ubiquitin Proteasome ◽  
Inhibitors Of Apoptosis Proteins ◽  
New Gene ◽  
Neuronal Precursor Cell ◽  
Apoptosis Proteins

AbstractThe inhibitors of apoptosis proteins (IAPs) are endogenous inhibitors for apoptosis. Apoptosis is carried out by caspases, which are the family of cystein proteases. IAPs regulate caspases through two conserved regions, the baculovirus IAP repeats (BIRs) and the really interesting new gene (RING) domains. Although the BIRs are responsible for binding to caspases, the RING domain can act as a ubiquitin-E3 ligase, leading to ubiquitylation of IAPs themselves and their pro-apoptotic IAP counterparts such as caspases. Recently, it is reported that another ubiquitin-like protein, neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8), is also involved in the regulation of apoptosis through neddylation of caspases mediated by IAPs. On the contrary, the results against the function of IAPs as a NEDD8-E3 ligase are also suggested. This review presents the summary of IAPs, caspases, and the ubiquitin-proteasome system and how their interactions influence the regulation of apoptosis.

scholarly journals The application of ubiquitin ligases in the PROTAC drug design

2020 ◽  
Vol 52 (7) ◽  
pp. 776-790 ◽  
Author(s):  
Yilin Chen ◽  
Jianping Jin
Keyword(s):  
Drug Design ◽  
Drug Targets ◽  
Recent Progress ◽  
Biological Activities ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Review Article ◽  
Main Process ◽  
Existing Problems ◽  
Ubiquitin Proteasome

Abstract Protein ubiquitylation plays important roles in many biological activities. Protein ubiquitylation is a unique process that is mainly controlled by ubiquitin ligases. The ubiquitin-proteasome system (UPS) is the main process to degrade short-lived and unwanted proteins in eukaryotes. Many components in the UPS are attractive drug targets. Recent studies indicated that ubiquitin ligases can be employed as tools in proteolysis-targeting chimeras (PROTACs) for drug discovery. In this review article, we will discuss the recent progress of the application of ubiquitin ligases in the PROTAC drug design. We will also discuss advantages and existing problems of PROTACs. Moreover, we will propose a few principles for selecting ubiquitin ligases in PROTAC applications.

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