Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization

Abstract ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults th...

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Main Authors:	Emile S. Pinarbasi, Tolga Cağatay, Ho Yee Joyce Fung, Ying C. Li, Yuh Min Chook, Philip J. Thomas
Format:	article
Language:	EN
Published:	Nature Portfolio 2018
Subjects:	Medicine R Science Q
Online Access:	https://doaj.org/article/e0bc0cffa6c242cf85832575acd6acd8
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spelling	oai:doaj.org-article:e0bc0cffa6c242cf85832575acd6acd82021-12-02T11:41:02ZActive nuclear import and passive nuclear export are the primary determinants of TDP-43 localization10.1038/s41598-018-25008-42045-2322https://doaj.org/article/e0bc0cffa6c242cf85832575acd6acd82018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25008-4https://doaj.org/toc/2045-2322Abstract ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied “∆NES” mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.Emile S. PinarbasiTolga CağatayHo Yee Joyce FungYing C. LiYuh Min ChookPhilip J. ThomasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-16 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emile S. Pinarbasi Tolga Cağatay Ho Yee Joyce Fung Ying C. Li Yuh Min Chook Philip J. Thomas Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
description	Abstract ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied “∆NES” mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.
format	article
author	Emile S. Pinarbasi Tolga Cağatay Ho Yee Joyce Fung Ying C. Li Yuh Min Chook Philip J. Thomas
author_facet	Emile S. Pinarbasi Tolga Cağatay Ho Yee Joyce Fung Ying C. Li Yuh Min Chook Philip J. Thomas
author_sort	Emile S. Pinarbasi
title	Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
title_short	Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
title_full	Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
title_fullStr	Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
title_full_unstemmed	Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
title_sort	active nuclear import and passive nuclear export are the primary determinants of tdp-43 localization
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e0bc0cffa6c242cf85832575acd6acd8
work_keys_str_mv	AT emilespinarbasi activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization AT tolgacagatay activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization AT hoyeejoycefung activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization AT yingcli activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization AT yuhminchook activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization AT philipjthomas activenuclearimportandpassivenuclearexportaretheprimarydeterminantsoftdp43localization
_version_	1718395490885697536

Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization

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