Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm
Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. Multiple FUS gene mutations have been linked to hereditary forms, and aggregation of FUS protein is believed to pl...
| Main Authors: | , , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
Landes Bioscience
2013
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865015/ |
| id |
pubmed-3865015 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-38650152013-12-23 Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm Shelkovnikova, Tatyana A Robinson, Hannah K Connor-Robson, Natalie Buchman, Vladimir L Report Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. Multiple FUS gene mutations have been linked to hereditary forms, and aggregation of FUS protein is believed to play an important role in pathogenesis of these diseases. In cultured cells, FUS variants with disease-associated amino acid substitutions or short deletions affecting nuclear localization signal (NLS) and causing cytoplasmic mislocalization can be sequestered into stress granules (SGs). We demonstrated that disruption of motifs responsible for RNA recognition and binding not only prevents SG recruitment, but also dramatically increases the protein propensity to aggregate in the cell cytoplasm with formation of juxtanuclear structures displaying typical features of aggresomes. Functional RNA-binding domains from TAR DNA-binding protein of 43 kDa (TDP-43) fused to highly aggregation-prone C-terminally truncated FUS protein restored the ability to enter SGs and prevented aggregation of the chimeric protein. Truncated FUS was also able to trap endogenous FUS molecules in the cytoplasmic aggregates. Our data indicate that RNA binding and recruitment to SGs protect cytoplasmic FUS from aggregation, and loss of this protection may trigger its pathological aggregation in vivo. Landes Bioscience 2013-10-01 2013-09-04 /pmc/articles/PMC3865015/ /pubmed/24013423 http://dx.doi.org/10.4161/cc.26241 Text en Copyright © 2013 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Shelkovnikova, Tatyana A Robinson, Hannah K Connor-Robson, Natalie Buchman, Vladimir L |
| spellingShingle |
Shelkovnikova, Tatyana A Robinson, Hannah K Connor-Robson, Natalie Buchman, Vladimir L Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| author_facet |
Shelkovnikova, Tatyana A Robinson, Hannah K Connor-Robson, Natalie Buchman, Vladimir L |
| author_sort |
Shelkovnikova, Tatyana A |
| title |
Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| title_short |
Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| title_full |
Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| title_fullStr |
Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| title_full_unstemmed |
Recruitment into stress granules prevents irreversible aggregation of FUS protein mislocalized to the cytoplasm |
| title_sort |
recruitment into stress granules prevents irreversible aggregation of fus protein mislocalized to the cytoplasm |
| description |
Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. Multiple FUS gene mutations have been linked to hereditary forms, and aggregation of FUS protein is believed to play an important role in pathogenesis of these diseases. In cultured cells, FUS variants with disease-associated amino acid substitutions or short deletions affecting nuclear localization signal (NLS) and causing cytoplasmic mislocalization can be sequestered into stress granules (SGs). We demonstrated that disruption of motifs responsible for RNA recognition and binding not only prevents SG recruitment, but also dramatically increases the protein propensity to aggregate in the cell cytoplasm with formation of juxtanuclear structures displaying typical features of aggresomes. Functional RNA-binding domains from TAR DNA-binding protein of 43 kDa (TDP-43) fused to highly aggregation-prone C-terminally truncated FUS protein restored the ability to enter SGs and prevented aggregation of the chimeric protein. Truncated FUS was also able to trap endogenous FUS molecules in the cytoplasmic aggregates. Our data indicate that RNA binding and recruitment to SGs protect cytoplasmic FUS from aggregation, and loss of this protection may trigger its pathological aggregation in vivo. |
| publisher |
Landes Bioscience |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865015/ |
| _version_ |
1612038869612494848 |