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Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformationa...

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Autores principales: Moon, Seonghyeon, Muniyappan, Srinivasan, Lee, Sung-Bae, Lee, Byung-Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226605/
https://www.ncbi.nlm.nih.gov/pubmed/34207520
http://dx.doi.org/10.3390/ijms22126213
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author Moon, Seonghyeon
Muniyappan, Srinivasan
Lee, Sung-Bae
Lee, Byung-Hoon
author_facet Moon, Seonghyeon
Muniyappan, Srinivasan
Lee, Sung-Bae
Lee, Byung-Hoon
author_sort Moon, Seonghyeon
collection PubMed
description The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases–USP14, RPN11, and UCH37–are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome’s conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.
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spelling pubmed-82266052021-06-26 Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases Moon, Seonghyeon Muniyappan, Srinivasan Lee, Sung-Bae Lee, Byung-Hoon Int J Mol Sci Review The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases–USP14, RPN11, and UCH37–are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome’s conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context. MDPI 2021-06-09 /pmc/articles/PMC8226605/ /pubmed/34207520 http://dx.doi.org/10.3390/ijms22126213 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Moon, Seonghyeon
Muniyappan, Srinivasan
Lee, Sung-Bae
Lee, Byung-Hoon
Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title_full Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title_fullStr Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title_full_unstemmed Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title_short Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases
title_sort small-molecule inhibitors targeting proteasome-associated deubiquitinases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226605/
https://www.ncbi.nlm.nih.gov/pubmed/34207520
http://dx.doi.org/10.3390/ijms22126213
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