Full metadata record
DC Field | Value | Language |
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dc.contributor.author | Boselli, Monica | - |
dc.contributor.author | Lee, Byung Hoon | - |
dc.contributor.author | Robert, Jessica | - |
dc.contributor.author | Prado, Miguel A. | - |
dc.contributor.author | Min, Sang-Won | - |
dc.contributor.author | Cheng, Chialin | - |
dc.contributor.author | Silva, M. Catarina | - |
dc.contributor.author | Seong, Changhyun | - |
dc.contributor.author | Elsasser, Suzanne | - |
dc.contributor.author | Hatle, Ketki M. | - |
dc.contributor.author | Gahman, Timothy C. | - |
dc.contributor.author | Gygi, Steven P. | - |
dc.contributor.author | Haggarty, Stephen J. | - |
dc.contributor.author | Gan, Li | - |
dc.contributor.author | King, Randall W. | - |
dc.contributor.author | Finley, Daniel | - |
dc.date.accessioned | 2018-02-05T04:12:22Z | - |
dc.date.available | 2018-02-05T04:12:22Z | - |
dc.date.created | 2018-01-01 | - |
dc.date.issued | 2017-11 | - |
dc.identifier.citation | Journal of Biological Chemistry, v.292, no.47, pp.19209 - 19225 | - |
dc.identifier.issn | 0021-9258 | - |
dc.identifier.uri | http://hdl.handle.net/20.500.11750/5638 | - |
dc.description.abstract | The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control and protein quality control. A component of this system, the deubiquitinating enzyme USP14, associates with the proteasome where it can rescue substrates from degradation by removal of the ubiquitin tag. We previously found that a small-molecule inhibitor of USP14, known as IU1, can increase the rate of degradation of a subset of proteasome substrates. We report here the synthesis and characterization of 87 variants of IU1, which resulted in the identification of a 10-fold more potent USP14 inhibitor that retains specificity for USP14. The capacity of this compound, IU1-47, to enhance protein degradation in cells was tested using as a reporter the microtubule-associated protein tau, which has been implicated in many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 was found to accelerate the rate of degradation of wild-type tau, the pathological tau mutants P301L and P301S, and the A152T tau variant. We also report that a specific residue in tau, lysine 174, is critical for the IU1-47-mediated tau degradation by the proteasome. Finally, we show that IU1-47 stimulates autophagic flux in primary neurons. In summary, these findings provide a powerful research tool for investigating the complex biology of USP14. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. | - |
dc.language | English | - |
dc.publisher | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | - |
dc.title | An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons | - |
dc.type | Article | - |
dc.identifier.doi | 10.1074/jbc.M117.815126 | - |
dc.identifier.wosid | 000416226700006 | - |
dc.identifier.scopusid | 2-s2.0-85032675934 | - |
dc.type.local | Article(Overseas) | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.citation.publicationname | Journal of Biological Chemistry | - |
dc.contributor.nonIdAuthor | Boselli, Monica | - |
dc.contributor.nonIdAuthor | Robert, Jessica | - |
dc.contributor.nonIdAuthor | Prado, Miguel A. | - |
dc.contributor.nonIdAuthor | Min, Sang-Won | - |
dc.contributor.nonIdAuthor | Cheng, Chialin | - |
dc.contributor.nonIdAuthor | Silva, M. Catarina | - |
dc.contributor.nonIdAuthor | Seong, Changhyun | - |
dc.contributor.nonIdAuthor | Elsasser, Suzanne | - |
dc.contributor.nonIdAuthor | Hatle, Ketki M. | - |
dc.contributor.nonIdAuthor | Gahman, Timothy C. | - |
dc.contributor.nonIdAuthor | Gygi, Steven P. | - |
dc.contributor.nonIdAuthor | Haggarty, Stephen J. | - |
dc.contributor.nonIdAuthor | Gan, Li | - |
dc.contributor.nonIdAuthor | King, Randall W. | - |
dc.contributor.nonIdAuthor | Finley, Daniel | - |
dc.identifier.citationVolume | 292 | - |
dc.identifier.citationNumber | 47 | - |
dc.identifier.citationStartPage | 19209 | - |
dc.identifier.citationEndPage | 19225 | - |
dc.identifier.citationTitle | Journal of Biological Chemistry | - |
dc.type.journalArticle | Article | - |
dc.description.isOpenAccess | N | - |
dc.subject.keywordAuthor | neurodegenerative disease | - |
dc.subject.keywordAuthor | proteasome | - |
dc.subject.keywordAuthor | small molecule | - |
dc.subject.keywordAuthor | tauopathy | - |
dc.subject.keywordAuthor | ubiquitin | - |
dc.subject.keywordAuthor | IU1 | - |
dc.subject.keywordAuthor | IU1-47 | - |
dc.subject.keywordPlus | UBIQUITIN-SPECIFIC PROTEASE | - |
dc.subject.keywordPlus | SMALL-MOLECULE INHIBITOR | - |
dc.subject.keywordPlus | ALZHEIMERS-DISEASE | - |
dc.subject.keywordPlus | FRONTOTEMPORAL DEMENTIA | - |
dc.subject.keywordPlus | 26S PROTEASOME | - |
dc.subject.keywordPlus | MEDIATED NEURODEGENERATION | - |
dc.subject.keywordPlus | TRANSGENIC MICE | - |
dc.subject.keywordPlus | ATAXIA MICE | - |
dc.subject.keywordPlus | DEGRADATION | - |
dc.subject.keywordPlus | AUTOPHAGY | - |
dc.contributor.affiliatedAuthor | Boselli, Monica | - |
dc.contributor.affiliatedAuthor | Lee, Byung Hoon | - |
dc.contributor.affiliatedAuthor | Robert, Jessica | - |
dc.contributor.affiliatedAuthor | Prado, Miguel A. | - |
dc.contributor.affiliatedAuthor | Min, Sang-Won | - |
dc.contributor.affiliatedAuthor | Cheng, Chialin | - |
dc.contributor.affiliatedAuthor | Silva, M. Catarina | - |
dc.contributor.affiliatedAuthor | Seong, Changhyun | - |
dc.contributor.affiliatedAuthor | Elsasser, Suzanne | - |
dc.contributor.affiliatedAuthor | Hatle, Ketki M. | - |
dc.contributor.affiliatedAuthor | Gahman, Timothy C. | - |
dc.contributor.affiliatedAuthor | Gygi, Steven P. | - |
dc.contributor.affiliatedAuthor | Haggarty, Stephen J. | - |
dc.contributor.affiliatedAuthor | Gan, Li | - |
dc.contributor.affiliatedAuthor | King, Randall W. | - |
dc.contributor.affiliatedAuthor | Finley, Daniel | - |