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HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19
Huntington’s disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interact...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666004/ https://www.ncbi.nlm.nih.gov/pubmed/29093475 http://dx.doi.org/10.1038/s41598-017-13711-7 |
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author | He, Wen-Tian Xue, Wei Gao, Yong-Guang Hong, Jun-Ye Yue, Hong-Wei Jiang, Lei-Lei Hu, Hong-Yu |
author_facet | He, Wen-Tian Xue, Wei Gao, Yong-Guang Hong, Jun-Ye Yue, Hong-Wei Jiang, Lei-Lei Hu, Hong-Yu |
author_sort | He, Wen-Tian |
collection | PubMed |
description | Huntington’s disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract. Structural integration of the middle and C-terminal domains of HSP90 is essential for interacting with Htt-N90, and the dimerization mediated by the C-terminal domain facilitates this interaction. Moreover, ubiquitin-specific protease 19 (USP19), a deubiquitinating enzyme interacting with HSP90, up-regulates the protein level of Htt-N90 and consequently promotes its aggregation, whereas disruption of the interaction between Htt-N90 and HSP90 attenuates the effect of USP19 on Htt-N90. Thus, HSP90 interacts with Htt-N90 on the N-terminal amphipathic α-helix, and then recruits USP19 to modulate the protein level and aggregation of Htt-N90. This study provides mechanistic insights into the recognition between HSP90 and the N-terminus of Htt, and the triage decision for the Htt protein by the HSP90 chaperone system. |
format | Online Article Text |
id | pubmed-5666004 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56660042017-11-08 HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 He, Wen-Tian Xue, Wei Gao, Yong-Guang Hong, Jun-Ye Yue, Hong-Wei Jiang, Lei-Lei Hu, Hong-Yu Sci Rep Article Huntington’s disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract. Structural integration of the middle and C-terminal domains of HSP90 is essential for interacting with Htt-N90, and the dimerization mediated by the C-terminal domain facilitates this interaction. Moreover, ubiquitin-specific protease 19 (USP19), a deubiquitinating enzyme interacting with HSP90, up-regulates the protein level of Htt-N90 and consequently promotes its aggregation, whereas disruption of the interaction between Htt-N90 and HSP90 attenuates the effect of USP19 on Htt-N90. Thus, HSP90 interacts with Htt-N90 on the N-terminal amphipathic α-helix, and then recruits USP19 to modulate the protein level and aggregation of Htt-N90. This study provides mechanistic insights into the recognition between HSP90 and the N-terminus of Htt, and the triage decision for the Htt protein by the HSP90 chaperone system. Nature Publishing Group UK 2017-11-01 /pmc/articles/PMC5666004/ /pubmed/29093475 http://dx.doi.org/10.1038/s41598-017-13711-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article He, Wen-Tian Xue, Wei Gao, Yong-Guang Hong, Jun-Ye Yue, Hong-Wei Jiang, Lei-Lei Hu, Hong-Yu HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title | HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title_full | HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title_fullStr | HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title_full_unstemmed | HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title_short | HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19 |
title_sort | hsp90 recognizes the n-terminus of huntingtin involved in regulation of huntingtin aggregation by usp19 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666004/ https://www.ncbi.nlm.nih.gov/pubmed/29093475 http://dx.doi.org/10.1038/s41598-017-13711-7 |
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