Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1

Abstract TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in...

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Autores principales:	Helena Ederle, Christina Funk, Claudia Abou-Ajram, Saskia Hutten, Eva B. E. Funk, Ralph H. Kehlenbach, Susanne M. Bailer, Dorothee Dormann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8094611fcf1f43b9ba32a1e651adbced
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spelling	oai:doaj.org-article:8094611fcf1f43b9ba32a1e651adbced2021-12-02T15:08:42ZNuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM110.1038/s41598-018-25007-52045-2322https://doaj.org/article/8094611fcf1f43b9ba32a1e651adbced2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25007-5https://doaj.org/toc/2045-2322Abstract TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology. Here we show that predicted nuclear export signals in TDP-43 and FUS are non-functional and that both proteins are exported independently of the export receptor CRM1/Exportin-1. Silencing of Exportin-5 or the mRNA export factor Aly/REF, as well as mutations that abrogate RNA-binding do not impair export of TDP-43 and FUS. However, artificially enlarging TDP-43 or FUS impairs their nuclear egress, suggesting that they could leave the nucleus by passive diffusion. Finally, we found that inhibition of transcription causes accelerated nuclear egress of TDP-43, suggesting that newly synthesized RNA retains TDP-43 in the nucleus, limiting its egress into the cytoplasm. Our findings implicate reduced nuclear retention as a possible factor contributing to mislocalization of TDP-43 in ALS/FTD.Helena EderleChristina FunkClaudia Abou-AjramSaskia HuttenEva B. E. FunkRalph H. KehlenbachSusanne M. BailerDorothee DormannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Helena Ederle Christina Funk Claudia Abou-Ajram Saskia Hutten Eva B. E. Funk Ralph H. Kehlenbach Susanne M. Bailer Dorothee Dormann Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
description	Abstract TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology. Here we show that predicted nuclear export signals in TDP-43 and FUS are non-functional and that both proteins are exported independently of the export receptor CRM1/Exportin-1. Silencing of Exportin-5 or the mRNA export factor Aly/REF, as well as mutations that abrogate RNA-binding do not impair export of TDP-43 and FUS. However, artificially enlarging TDP-43 or FUS impairs their nuclear egress, suggesting that they could leave the nucleus by passive diffusion. Finally, we found that inhibition of transcription causes accelerated nuclear egress of TDP-43, suggesting that newly synthesized RNA retains TDP-43 in the nucleus, limiting its egress into the cytoplasm. Our findings implicate reduced nuclear retention as a possible factor contributing to mislocalization of TDP-43 in ALS/FTD.
format	article
author	Helena Ederle Christina Funk Claudia Abou-Ajram Saskia Hutten Eva B. E. Funk Ralph H. Kehlenbach Susanne M. Bailer Dorothee Dormann
author_facet	Helena Ederle Christina Funk Claudia Abou-Ajram Saskia Hutten Eva B. E. Funk Ralph H. Kehlenbach Susanne M. Bailer Dorothee Dormann
author_sort	Helena Ederle
title	Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
title_short	Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
title_full	Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
title_fullStr	Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
title_full_unstemmed	Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1
title_sort	nuclear egress of tdp-43 and fus occurs independently of exportin-1/crm1
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/8094611fcf1f43b9ba32a1e651adbced
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_version_	1718388069756829696

Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1

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