Cargando…

CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons

For proper function of proteins, their subcellular localization needs to be monitored and regulated in response to the changes in cellular demands. In this regard, dysregulation in the nucleocytoplasmic transport (NCT) of proteins is closely associated with the pathogenesis of various neurodegenerat...

Descripción completa

Detalles Bibliográficos
Autores principales: Cho, Jae Ho, Jo, Min Gu, Kim, Eun Seon, Lee, Na Yoon, Kim, Soon Ha, Chung, Chang Geon, Park, Jeong Hyang, Lee, Sung Bae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Molecular and Cellular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676984/
https://www.ncbi.nlm.nih.gov/pubmed/36172977
http://dx.doi.org/10.14348/molcells.2022.0104
_version_ 1784833712916004864
author Cho, Jae Ho
Jo, Min Gu
Kim, Eun Seon
Lee, Na Yoon
Kim, Soon Ha
Chung, Chang Geon
Park, Jeong Hyang
Lee, Sung Bae
author_facet Cho, Jae Ho
Jo, Min Gu
Kim, Eun Seon
Lee, Na Yoon
Kim, Soon Ha
Chung, Chang Geon
Park, Jeong Hyang
Lee, Sung Bae
author_sort Cho, Jae Ho
collection PubMed
description For proper function of proteins, their subcellular localization needs to be monitored and regulated in response to the changes in cellular demands. In this regard, dysregulation in the nucleocytoplasmic transport (NCT) of proteins is closely associated with the pathogenesis of various neurodegenerative diseases. However, it remains unclear whether there exists an intrinsic regulatory pathway(s) that controls NCT of proteins either in a commonly shared manner or in a target-selectively different manner. To dissect between these possibilities, in the current study, we investigated the molecular mechanism regulating NCT of truncated ataxin-3 (ATXN3) proteins of which genetic mutation leads to a type of polyglutamine (polyQ) diseases, in comparison with that of TDP-43. In Drosophila dendritic arborization (da) neurons, we observed dynamic changes in the subcellular localization of truncated ATXN3 proteins between the nucleus and the cytosol during development. Moreover, ectopic neuronal toxicity was induced by truncated ATXN3 proteins upon their nuclear accumulation. Consistent with a previous study showing intracellular calcium-dependent NCT of TDP-43, NCT of ATXN3 was also regulated by intracellular calcium level and involves Importin α3 (Imp α3). Interestingly, NCT of ATXN3, but not TDP-43, was primarily mediated by CBP. We further showed that acetyltransferase activity of CBP is important for NCT of ATXN3, which may acetylate Imp α3 to regulate NCT of ATXN3. These findings demonstrate that CBP-dependent acetylation of Imp α3 is crucial for intracellular calcium-dependent NCT of ATXN3 proteins, different from that of TDP-43, in Drosophila neurons.
format Online
Article
Text
id pubmed-9676984
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Korean Society for Molecular and Cellular Biology
record_format MEDLINE/PubMed
spelling pubmed-96769842022-11-30 CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons Cho, Jae Ho Jo, Min Gu Kim, Eun Seon Lee, Na Yoon Kim, Soon Ha Chung, Chang Geon Park, Jeong Hyang Lee, Sung Bae Mol Cells Research Article For proper function of proteins, their subcellular localization needs to be monitored and regulated in response to the changes in cellular demands. In this regard, dysregulation in the nucleocytoplasmic transport (NCT) of proteins is closely associated with the pathogenesis of various neurodegenerative diseases. However, it remains unclear whether there exists an intrinsic regulatory pathway(s) that controls NCT of proteins either in a commonly shared manner or in a target-selectively different manner. To dissect between these possibilities, in the current study, we investigated the molecular mechanism regulating NCT of truncated ataxin-3 (ATXN3) proteins of which genetic mutation leads to a type of polyglutamine (polyQ) diseases, in comparison with that of TDP-43. In Drosophila dendritic arborization (da) neurons, we observed dynamic changes in the subcellular localization of truncated ATXN3 proteins between the nucleus and the cytosol during development. Moreover, ectopic neuronal toxicity was induced by truncated ATXN3 proteins upon their nuclear accumulation. Consistent with a previous study showing intracellular calcium-dependent NCT of TDP-43, NCT of ATXN3 was also regulated by intracellular calcium level and involves Importin α3 (Imp α3). Interestingly, NCT of ATXN3, but not TDP-43, was primarily mediated by CBP. We further showed that acetyltransferase activity of CBP is important for NCT of ATXN3, which may acetylate Imp α3 to regulate NCT of ATXN3. These findings demonstrate that CBP-dependent acetylation of Imp α3 is crucial for intracellular calcium-dependent NCT of ATXN3 proteins, different from that of TDP-43, in Drosophila neurons. Korean Society for Molecular and Cellular Biology 2022-11-30 2022-09-28 /pmc/articles/PMC9676984/ /pubmed/36172977 http://dx.doi.org/10.14348/molcells.2022.0104 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. https://creativecommons.org/licenses/by-nc-sa/3.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ (https://creativecommons.org/licenses/by-nc-sa/3.0/)
spellingShingle Research Article
Cho, Jae Ho
Jo, Min Gu
Kim, Eun Seon
Lee, Na Yoon
Kim, Soon Ha
Chung, Chang Geon
Park, Jeong Hyang
Lee, Sung Bae
CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title_full CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title_fullStr CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title_full_unstemmed CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title_short CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons
title_sort cbp-mediated acetylation of importin α mediates calcium-dependent nucleocytoplasmic transport of selective proteins in drosophila neurons
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676984/
https://www.ncbi.nlm.nih.gov/pubmed/36172977
http://dx.doi.org/10.14348/molcells.2022.0104
work_keys_str_mv AT chojaeho cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT jomingu cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT kimeunseon cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT leenayoon cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT kimsoonha cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT chungchanggeon cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT parkjeonghyang cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons
AT leesungbae cbpmediatedacetylationofimportinamediatescalciumdependentnucleocytoplasmictransportofselectiveproteinsindrosophilaneurons