Header

UZH-Logo

Maintenance Infos

Nuclear import receptors directly bind to arginine-rich dipeptide repeat proteins and suppress their pathological interactions


Hutten, Saskia; Usluer, Sinem; Bourgeois, Benjamin; Simonetti, Francesca; Odeh, Hana M; Fare, Charlotte M; Czuppa, Mareike; Hruska-Plochan, Marian; Hofweber, Mario; Polymenidou, Magdalini; Shorter, James; Edbauer, Dieter; Madl, Tobias; Dormann, Dorothee (2020). Nuclear import receptors directly bind to arginine-rich dipeptide repeat proteins and suppress their pathological interactions. Cell Reports, 33(12):108538.

Abstract

Nuclear import receptors, also called importins, mediate nuclear import of proteins and chaperone aggregation-prone cargoes (e.g., neurodegeneration-linked RNA-binding proteins [RBPs]) in the cytoplasm. Importins were identified as modulators of cellular toxicity elicited by arginine-rich dipeptide repeat proteins (DPRs), an aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mechanistically, the link between importins and arginine-rich DPRs remains unclear. Here, we show that arginine-rich DPRs (poly-GR and poly-PR) bind directly to multiple importins and, in excess, promote their insolubility and condensation. In cells, poly-GR impairs Impα/β-mediated nuclear import, including import of TDP-43, an RBP that aggregates in C9orf72-ALS/FTD patients. Arginine-rich DPRs promote phase separation and insolubility of TDP-43 in vitro and in cells, and this pathological interaction is suppressed by elevating importin concentrations. Our findings suggest that importins can decrease toxicity of arginine-rich DPRs by suppressing their pathological interactions.

Abstract

Nuclear import receptors, also called importins, mediate nuclear import of proteins and chaperone aggregation-prone cargoes (e.g., neurodegeneration-linked RNA-binding proteins [RBPs]) in the cytoplasm. Importins were identified as modulators of cellular toxicity elicited by arginine-rich dipeptide repeat proteins (DPRs), an aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mechanistically, the link between importins and arginine-rich DPRs remains unclear. Here, we show that arginine-rich DPRs (poly-GR and poly-PR) bind directly to multiple importins and, in excess, promote their insolubility and condensation. In cells, poly-GR impairs Impα/β-mediated nuclear import, including import of TDP-43, an RBP that aggregates in C9orf72-ALS/FTD patients. Arginine-rich DPRs promote phase separation and insolubility of TDP-43 in vitro and in cells, and this pathological interaction is suppressed by elevating importin concentrations. Our findings suggest that importins can decrease toxicity of arginine-rich DPRs by suppressing their pathological interactions.

Statistics

Citations

Dimensions.ai Metrics
11 citations in Web of Science®
8 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

7 downloads since deposited on 25 Jan 2021
7 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, ALS; FTD; TDP-43; chaperone; dipeptide repeat proteins; importin; nneurodegeneration; nuclear import receptor; nuclear transport receptor; phase separation.
Language:English
Date:1 December 2020
Deposited On:25 Jan 2021 15:18
Last Modified:28 Jan 2021 19:09
Publisher:Cell Press (Elsevier)
ISSN:2211-1247
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.celrep.2020.108538

Download

Gold Open Access

Download PDF  'Nuclear import receptors directly bind to arginine-rich dipeptide repeat proteins and suppress their pathological interactions'.
Preview
Content: Published Version
Language: English
Filetype: PDF
Size: 3MB
View at publisher
Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)