scholarly journals Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets

2010 ◽  
Vol 10 (1) ◽  
pp. 29-46 ◽  
Author(s):  
Lynn Bedford ◽  
James Lowe ◽  
Lawrence R. Dick ◽  
R. John Mayer ◽  
James E. Brownell
Keyword(s):  
Drug Targets ◽  
Ubiquitin Proteasome System ◽  
Protein Conjugation ◽  
Ubiquitin Proteasome

scholarly journals The ubiquitin proteasome system in synaptic and axonal degeneration

2004 ◽  
Vol 165 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Laura Korhonen ◽  
Dan Lindholm
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Targets ◽  
Axonal Degeneration ◽  
Fruit Fly ◽  
Ubiquitin Proteasome System ◽  
Synaptic Protein ◽  
Ubiquitin Proteasome ◽  
Novel Drug ◽  
Novel Drug Targets

The ubiquitin proteasome system (UPS) contributes to the pathophysiology of neurodegenerative diseases, and it is also a major determinant of synaptic protein degradation and activity. Recent studies in rodents and in the fruit fly Drosophila have shown that the activity of the UPS is involved in axonal degeneration. Increased knowledge of the UPS in synaptic and axonal reactions may provide novel drug targets for treatments of neuronal injuries and neurodegenerative disorders.

scholarly journals The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Mónika Lippai ◽  
Péter Lőw
Keyword(s):  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Intracellular Pathogens ◽  
Protein Conjugation ◽  
Cytosolic Proteins ◽  
Ubiquitin Binding ◽  
Ubiquitin Proteasome ◽  
Point Of Intersection

The ubiquitin-proteasome system and autophagy were long viewed as independent, parallel degradation systems with no point of intersection. By now we know that these degradation pathways share certain substrates and regulatory molecules and show coordinated and compensatory function. Two ubiquitin-like protein conjugation pathways were discovered that are required for autophagosome biogenesis: the Atg12-Atg5-Atg16 and Atg8 systems. Autophagy has been considered to be essentially a nonselective process, but it turned out to be at least partially selective. Selective substrates of autophagy include damaged mitochondria, intracellular pathogens, and even a subset of cytosolic proteins with the help of ubiquitin-binding autophagic adaptors, such as p62/SQSTM1, NBR1, NDP52, and Optineurin. These proteins selectively recognize autophagic cargo and mediate its engulfment into autophagosomes by binding to the small ubiquitin-like modifiers that belong to the Atg8/LC3 family.

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 Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 607
Author(s):  
Soonsil Hyun ◽  
Dongyun Shin
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Drug Targets ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Therapeutic Modality ◽  
Target Proteins ◽  
Bifunctional Molecules ◽  
Ubiquitin Proteasome ◽  
Related Proteins

Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases.

scholarly journals Ubiquitination and the Proteasome as Drug Targets in Trypanosomatid Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Marie-José Bijlmakers
Keyword(s):  
Drug Targets ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Efficacy And Safety ◽  
Cellular Processes ◽  
Therapeutic Drugs ◽  
Selective Targeting ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Novel Drug

The eukaryotic pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania are responsible for debilitating diseases that affect millions of people worldwide. The numbers of drugs available to treat these diseases, Human African Trypanosomiasis, Chagas' disease and Leishmaniasis are very limited and existing treatments have substantial shortcomings in delivery method, efficacy and safety. The identification and validation of novel drug targets opens up new opportunities for the discovery of therapeutic drugs with better efficacy and safety profiles. Here, the potential of targeting the ubiquitin-proteasome system in these parasites is reviewed. Ubiquitination is the posttranslational attachment of one or more ubiquitin proteins to substrates, an essential eukaryotic mechanism that regulates a wide variety of cellular processes in many different ways. The best studied of these is the delivery of ubiquitinated substrates for degradation to the proteasome, the major cellular protease. However, ubiquitination can also regulate substrates in proteasome-independent ways, and proteasomes can degrade proteins to some extent in ubiquitin-independent ways. Because of these widespread roles, both ubiquitination and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well.

Emerging Role of the Ubiquitin-proteasome System as Drug Targets

2013 ◽  
Vol 19 (18) ◽  
pp. 3175-3189 ◽  
Author(s):  
Gozde Kar ◽  
Ozlem Keskin ◽  
Franca Fraternali ◽  
Attila Gursoy
Keyword(s):  
Drug Targets ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

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.

USP15 antagonizes CRL4CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates

2021 ◽  
Vol 118 (40) ◽  
pp. e2111391118
Author(s):  
Thang Van Nguyen
Keyword(s):  
Glutamine Synthetase ◽  
Drug Targets ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Intrinsic Resistance ◽  
New Strategy ◽  
Therapeutic Opportunity ◽  
Ubiquitin Proteasome ◽  
Control Stability ◽  
Almost All

Targeted protein degradation by the ubiquitin–proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs). Despite recent advances in developing potent CELMoDs and CRBN-based proteolysis-targeting chimeras (PROTACs), many questions apart from clinical efficacy remain unanswered. CRBN is required for the action of IMiDs, but its protein expression levels do not correlate with intrinsic resistance to IMiDs in MM cells, suggesting other factors involved in regulating resistance to IMiDs. Our recent work revealed that the CRL4CRBN-p97 pathway is required for degradation of natural substrate glutamine synthetase (GS) and neosubstrates. Here, I show that USP15 is a key regulator of the CRL4CRBN-p97 pathway to control stability of GS and neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4, all of which are crucial drug targets in different types of cancer. USP15 antagonizes ubiquitylation of CRL4CRBN target proteins, thereby preventing their degradation. Notably, USP15 is highly expressed in IMiD-resistant cells, and depletion of USP15 sensitizes these cells to lenalidomide. Inhibition of USP15 represents a valuable therapeutic opportunity to potentiate CELMoD and CRBN-based PROTAC therapies for the treatment of cancer.

scholarly journals Irf2bp2a regulates terminal granulopoiesis through proteasomal degradation of Gfi1aa in zebrafish

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009693
Author(s):  
Shuo Gao ◽  
Zixuan Wang ◽  
Luxiang Wang ◽  
Haihong Wang ◽  
Hao Yuan ◽  
...  
Keyword(s):  
Drug Targets ◽  
Ring Finger ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Link Type ◽  
Ubiquitin E3 Ligase ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Transcription Regulators

The ubiquitin-proteasome system plays important roles in various biological processes as it degrades the majority of cellular proteins. Adequate proteasomal degradation of crucial transcription regulators ensures the proper development of neutrophils. The ubiquitin E3 ligase of Growth factor independent 1 (GFI1), a key transcription repressor governing terminal granulopoiesis, remains obscure. Here we report that the deficiency of the ring finger protein Interferon regulatory factor 2 binding protein 2a (Irf2bp2a) leads to an impairment of neutrophils differentiation in zebrafish. Mechanistically, Irf2bp2a functions as a ubiquitin E3 ligase targeting Gfi1aa for proteasomal degradation. Moreover, irf2bp2a gene is repressed by Gfi1aa, thus forming a negative feedback loop between Irf2bp2a and Gfi1aa during neutrophils maturation. Different levels of GFI1 may turn it into a tumor suppressor or an oncogene in malignant myelopoiesis. Therefore, discovery of certain drug targets GFI1 for proteasomal degradation by IRF2BP2 might be an effective anti-cancer strategy.

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