Cargando…

Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates

Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington’s disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nuc...

Descripción completa

Detalles Bibliográficos
Autores principales: Mano, Tatsuo, Suzuki, Takayoshi, Tsuji, Shoji, Iwata, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224383/
https://www.ncbi.nlm.nih.gov/pubmed/25380050
http://dx.doi.org/10.1371/journal.pone.0111277
_version_ 1782343336858746880
author Mano, Tatsuo
Suzuki, Takayoshi
Tsuji, Shoji
Iwata, Atsushi
author_facet Mano, Tatsuo
Suzuki, Takayoshi
Tsuji, Shoji
Iwata, Atsushi
author_sort Mano, Tatsuo
collection PubMed
description Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington’s disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addition to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amount of Htt aggregates by increasing the amount of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation.
format Online
Article
Text
id pubmed-4224383
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-42243832014-11-18 Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates Mano, Tatsuo Suzuki, Takayoshi Tsuji, Shoji Iwata, Atsushi PLoS One Research Article Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington’s disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addition to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amount of Htt aggregates by increasing the amount of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation. Public Library of Science 2014-11-07 /pmc/articles/PMC4224383/ /pubmed/25380050 http://dx.doi.org/10.1371/journal.pone.0111277 Text en © 2014 Mano et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mano, Tatsuo
Suzuki, Takayoshi
Tsuji, Shoji
Iwata, Atsushi
Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title_full Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title_fullStr Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title_full_unstemmed Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title_short Differential Effect of HDAC3 on Cytoplasmic and Nuclear Huntingtin Aggregates
title_sort differential effect of hdac3 on cytoplasmic and nuclear huntingtin aggregates
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224383/
https://www.ncbi.nlm.nih.gov/pubmed/25380050
http://dx.doi.org/10.1371/journal.pone.0111277
work_keys_str_mv AT manotatsuo differentialeffectofhdac3oncytoplasmicandnuclearhuntingtinaggregates
AT suzukitakayoshi differentialeffectofhdac3oncytoplasmicandnuclearhuntingtinaggregates
AT tsujishoji differentialeffectofhdac3oncytoplasmicandnuclearhuntingtinaggregates
AT iwataatsushi differentialeffectofhdac3oncytoplasmicandnuclearhuntingtinaggregates