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

Abstract

AbstractTDP-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.

Autoren

Helena Ederle
Christina Funk
Claudia Abou-Ajram
Saskia Hutten
Eva BE Funk
Ralph H Kehlenbach
Susanne M Bailer
Dorothee Dormann

DOI

10.1038/s41598-018-25007-5

eISSN

2045-2322

Ausgabe der Veröffentlichung

1

Zeitschrift

Scientific Reports

Sprache

en

Artikelnummer

7084

Online publication date

2018

Status

Published online

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1038/s41598-018-25007-5

Datum der Datenerfassung

2022

Titel

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

Ausgabe der Zeitschrift

8

Data source: Crossref

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.

Addresses

BioMedical Center (BMC), Cell Biology, Ludwig-Maximilians-University Munich, 82152, Planegg-Martinsried, Germany.

Autoren

Helena Ederle
Christina Funk
Claudia Abou-Ajram
Saskia Hutten
Eva BE Funk
Ralph H Kehlenbach
Susanne M Bailer
Dorothee Dormann

DOI

10.1038/s41598-018-25007-5

eISSN

2045-2322

Externe Identifier

PubMed Identifier: 29728564
PubMed Central ID: PMC5935713

Open access

true

ISSN

2045-2322

Ausgabe der Veröffentlichung

1

Zeitschrift

Scientific reports

Schlüsselwörter

Cell Nucleus
Humans
Protein Sorting Signals
Karyopherins
RNA-Binding Protein FUS
DNA-Binding Proteins
Receptors, Cytoplasmic and Nuclear
RNA, Messenger
Protein Binding
Protein Transport
Exportin 1 Protein

Sprache

eng

Medium

Electronic

Online publication date

2018

Open access status

Open Access

Paginierung

7084

Datum der Veröffentlichung

2018

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2018

Titel

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

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

8

Files

https://www.nature.com/articles/s41598-018-25007-5.pdf https://europepmc.org/articles/PMC5935713?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2018

Autoren

Helena Ederle
Christina Funk
Claudia Abou-Ajram
Saskia Hutten
Eva BE Funk
Ralph H Kehlenbach
Susanne M Bailer
Dorothee Dormann

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/29728564

DOI

10.1038/s41598-018-25007-5

eISSN

2045-2322

Externe Identifier

PubMed Central ID: PMC5935713

Ausgabe der Veröffentlichung

1

Zeitschrift

Sci Rep

Schlüsselwörter

Cell Nucleus
DNA-Binding Proteins
Humans
Karyopherins
Protein Binding
Protein Sorting Signals
Protein Transport
RNA, Messenger
RNA-Binding Protein FUS
Receptors, Cytoplasmic and Nuclear
Exportin 1 Protein

Sprache

eng

Country

England

Paginierung

7084

PII

10.1038/s41598-018-25007-5

Datum der Veröffentlichung

2018

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2019

Titel

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

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

8

Data source: PubMed

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

Files

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