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Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity
The ubiquitin-proteasome system (UPS) is the primary mechanism by which intracellular proteins, transcription factors, and many proteotoxic proteins with aggregation-prone structures are degraded. The UPS is reportedly downregulated in various neurodegenerative disorders, with increased proteasome a...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455164/ https://www.ncbi.nlm.nih.gov/pubmed/26041011 http://dx.doi.org/10.1038/srep10757 |
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author | Lee, Jung Hoon Shin, Seung Kyun Jiang, Yanxialei Choi, Won Hoon Hong, Chaesun Kim, Dong-Eun Lee, Min Jae |
author_facet | Lee, Jung Hoon Shin, Seung Kyun Jiang, Yanxialei Choi, Won Hoon Hong, Chaesun Kim, Dong-Eun Lee, Min Jae |
author_sort | Lee, Jung Hoon |
collection | PubMed |
description | The ubiquitin-proteasome system (UPS) is the primary mechanism by which intracellular proteins, transcription factors, and many proteotoxic proteins with aggregation-prone structures are degraded. The UPS is reportedly downregulated in various neurodegenerative disorders, with increased proteasome activity shown to be beneficial in many related disease models. Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB). We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. Our results indicate that these novel inhibitory UPS14 aptamers can be used to enhance proteasome activity, and to facilitate the degradation of proteotoxic proteins, thereby protecting cells from various neurodegenerative stressors. |
format | Online Article Text |
id | pubmed-4455164 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-44551642015-06-10 Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity Lee, Jung Hoon Shin, Seung Kyun Jiang, Yanxialei Choi, Won Hoon Hong, Chaesun Kim, Dong-Eun Lee, Min Jae Sci Rep Article The ubiquitin-proteasome system (UPS) is the primary mechanism by which intracellular proteins, transcription factors, and many proteotoxic proteins with aggregation-prone structures are degraded. The UPS is reportedly downregulated in various neurodegenerative disorders, with increased proteasome activity shown to be beneficial in many related disease models. Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB). We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. Our results indicate that these novel inhibitory UPS14 aptamers can be used to enhance proteasome activity, and to facilitate the degradation of proteotoxic proteins, thereby protecting cells from various neurodegenerative stressors. Nature Publishing Group 2015-06-04 /pmc/articles/PMC4455164/ /pubmed/26041011 http://dx.doi.org/10.1038/srep10757 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Lee, Jung Hoon Shin, Seung Kyun Jiang, Yanxialei Choi, Won Hoon Hong, Chaesun Kim, Dong-Eun Lee, Min Jae Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title | Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title_full | Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title_fullStr | Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title_full_unstemmed | Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title_short | Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity |
title_sort | facilitated tau degradation by usp14 aptamers via enhanced proteasome activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455164/ https://www.ncbi.nlm.nih.gov/pubmed/26041011 http://dx.doi.org/10.1038/srep10757 |
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