Inhibition of the ubiquitin-proteasome system: a new avenue for atherosclerosis

2006 ◽  
Vol 44 (10) ◽  
Author(s):  
Chunjiang Tan ◽  
Yuguang Li ◽  
Xuerui Tan ◽  
Hongxin Pan ◽  
Wen Huang
Keyword(s):  
Ubiquitin Proteasome System ◽  
System A ◽  
Ubiquitin Proteasome

AbstractClin Chem Lab Med 2006;44:1218–25.

scholarly journals Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

2021 ◽  
Vol 22 (16) ◽  
pp. 8944
Author(s):  
Sean M. Cascarina ◽  
Joshua P. Kaplan ◽  
Mikaela R. Elder ◽  
Lindsey Brookbank ◽  
Eric D. Ross
Keyword(s):  
Protein Aggregation ◽  
Ubiquitin Proteasome System ◽  
Low Complexity ◽  
Hydrophobic Residues ◽  
System A ◽  
Polar Low ◽  
Eukaryotic Proteomes ◽  
Ubiquitin Proteasome ◽  
Folded Proteins ◽  
Aggregation Activity

Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.

scholarly journals The ubiquitin-proteasome system: A novel target for anticancer and anti-inflammatory drug research

2008 ◽  
Vol 13 (3) ◽  
Author(s):  
Halina Ostrowska
Keyword(s):  
Cell Cycle Progression ◽  
Control Cell ◽  
Ubiquitin Proteasome System ◽  
Cycle Progression ◽  
System A ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Novel Target ◽  
Transcriptional Pathway ◽  
Control Cell Cycle Progression

AbstractThe ubiquitin-proteasome system is responsible for the degradation of most intracellular proteins, including those that control cell cycle progression, apoptosis, signal transduction and the NF-κB transcriptional pathway. Aberrations in the ubiquitin-proteasome system underlie the pathogenesis of many human diseases, so both the ubiquitin-conjugating system and the 20S proteasome are important targets for drug discovery. This article presents a few of the most important examples of the small molecule inhibitors and modulators targeting the ubiquitin-proteasome system, their mode of action, and their potential therapeutic relevance in the treatment of cancer and inflammatory-related diseases.

scholarly journals ATGGenes Influence the Virulence ofCryptococcus neoformansthrough Contributions beyond Core Autophagy Functions

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Hao Ding ◽  
Mélissa Caza ◽  
Yifei Dong ◽  
Arif A. Arif ◽  
Linda C. Horianopoulos ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nutrient Recycling ◽  
Ubiquitin Proteasome System ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
System A ◽  
Ubiquitin Proteasome ◽  
Amino Acid Homeostasis ◽  
Virulence Factor Production

ABSTRACTThe process of autophagy is conserved among all eukaryotes from yeast to humans and is mainly responsible for bulk degradation of cellular contents and nutrient recycling during starvation. Autophagy has been suggested to play a role in the pathogenesis of the opportunistic human fungal pathogenCryptococcus neoformans, potentially through a contribution to the export of virulence factors. In this study, we showed that deletion of each of theATG1,ATG7,ATG8, andATG9genes inC. neoformansleads to autophagy-related phenotypes, including impaired amino acid homeostasis under nitrogen starvation. In addition, theatgΔ mutants were hypersensitive to inhibition of the ubiquitin-proteasome system, a finding consistent with a role in amino acid homeostasis. Although eachatgΔ mutant was not markedly impaired in virulence factor productionin vitro, we found that all fourATGgenes contribute toC. neoformansvirulence in a murine inhalation model of cryptococcosis. Interestingly, these mutants displayed significant differences in their ability to promote disease development. A more detailed investigation of virulence for theatg1Δ andatg8Δ mutants revealed that both strains stimulated an exaggerated host immune response, which, in turn, contributed to disease severity. Overall, our results suggest that differentATGgenes are involved in nonautophagic functions and contribute toC. neoformansvirulence beyond their core functions in autophagy.

Skp2 in the ubiquitin‐proteasome system: A comprehensive review

2020 ◽  
Vol 40 (5) ◽  
pp. 1920-1949 ◽  
Author(s):  
Moges Dessale Asmamaw ◽  
Ying Liu ◽  
Yi‐Chao Zheng ◽  
Xiao‐Jing Shi ◽  
Hong‐Min Liu
Keyword(s):  
Ubiquitin Proteasome System ◽  
Comprehensive Review ◽  
System A ◽  
Ubiquitin Proteasome

scholarly journals HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 133 ◽  
Author(s):  
Anamaria Đukić ◽  
Lucija Lulić ◽  
Miranda Thomas ◽  
Josipa Skelin ◽  
Nathaniel Edward Bennett Saidu ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Cellular Functions ◽  
Hpv E6 ◽  
System A ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
Hpv Oncoproteins ◽  
Regulation Of Cell Cycle

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer.

The ubiquitin-proteasome system: A potential therapeutic target for heart failure

2017 ◽  
Vol 36 (7) ◽  
pp. 708-714 ◽  
Author(s):  
Yaron D. Barac ◽  
Fabian Emrich ◽  
Efrat Krutzwakd-Josefson ◽  
Sonja Schrepfer ◽  
Luiz C. Sampaio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Therapeutic Target ◽  
Ubiquitin Proteasome System ◽  
Potential Therapeutic Target ◽  
System A ◽  
Ubiquitin Proteasome

scholarly journals Selective targeting of non-centrosomal AURKA functions through use of a novel targeted protein degradation tool

2020 ◽  
Author(s):  
Richard Wang ◽  
Ahmed Abdelbaki ◽  
Camilla Ascanelli ◽  
Alex Fung ◽  
Tim Rasmusson ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cell Biology ◽  
Mitochondrial Dynamics ◽  
Functional Characterization ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Modality ◽  
System A ◽  
Small Molecule Ligands ◽  
Ubiquitin Proteasome ◽  
Clinical Interest

AbstractTargeted protein degradation tools are becoming a new therapeutic modality, allowing small molecule ligands to be reformulated as heterobifunctional molecules (referred to as ‘PROTACs’, for PROteolysis Targeting Chimeras) that recruit a ubiquitin ligase to the target of interest, leading to ubiquitination of the target and its destruction via the ubiquitin-proteasome system. A number of PROTACs against targets of clinical interest have been described, but detailed descriptions of the cell biology modulated by PROTACs are missing from the literature. Here we describe the functional characterization of a PROTAC derived from AURKA inhibitor MLN8237 (alisertib). We demonstrate efficient and specific destruction of both endogenous and overexpressed AURKA by Cereblon-directed PROTACs. At the subcellular level, we find differential targeting of AURKA on the mitotic spindle compared to centrosomes. The phenotypic consequences of PROTAC treatment are therefore distinct from those mediated by alisertib, and in mitotic cells differentially regulate the centrosome- and chromatin-based microtubule spindle assembly pathways. In interphase cells we find that PROTAC-mediated clearance of non-centrosomal AURKA, and not PROTAC-mediated inhibition of its activity, efficiently modulates the cytoplasmic role played by AURKA in mitochondrial dynamics, whilst the centrosomal pool is refractory to PROTAC-mediated clearance. Our results point to differential accessibility of subcellular pools of substrate, governed by substrate conformation or localization in compartments more or less accessible to PROTAC action, a phenomenon not previously described for this new class of drugs.

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