Cargando…

Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients

Myotonic dystrophy (DM1) is caused by an expansion of CUG repeats (CUG(exp)) in the DMPK mRNA 3′UTR. CUG(exp)-containing mRNAs become toxic to cells by misregulating RNA-binding proteins. Here we investigated the consequence of this RNA toxicity on the cellular stress response. We report that cell s...

Descripción completa

Detalles Bibliográficos
Autores principales: Ravel-Chapuis, Aymeric, Klein Gunnewiek, Amanda, Bélanger, Guy, Crawford Parks, Tara E., Côté, Jocelyn, Jasmin, Bernard J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884064/
https://www.ncbi.nlm.nih.gov/pubmed/27030674
http://dx.doi.org/10.1091/mbc.E15-06-0356
_version_ 1782434331336114176
author Ravel-Chapuis, Aymeric
Klein Gunnewiek, Amanda
Bélanger, Guy
Crawford Parks, Tara E.
Côté, Jocelyn
Jasmin, Bernard J.
author_facet Ravel-Chapuis, Aymeric
Klein Gunnewiek, Amanda
Bélanger, Guy
Crawford Parks, Tara E.
Côté, Jocelyn
Jasmin, Bernard J.
author_sort Ravel-Chapuis, Aymeric
collection PubMed
description Myotonic dystrophy (DM1) is caused by an expansion of CUG repeats (CUG(exp)) in the DMPK mRNA 3′UTR. CUG(exp)-containing mRNAs become toxic to cells by misregulating RNA-binding proteins. Here we investigated the consequence of this RNA toxicity on the cellular stress response. We report that cell stress efficiently triggers formation of stress granules (SGs) in proliferating, quiescent, and differentiated muscle cells, as shown by the appearance of distinct cytoplasmic TIA-1– and DDX3-containing foci. We show that Staufen1 is also dynamically recruited into these granules. Moreover, we discovered that DM1 myoblasts fail to properly form SGs in response to arsenite. This blockage was not observed in DM1 fibroblasts, demonstrating a cell type–specific defect. DM1 myoblasts display increased expression and sequestration of toxic CUG(exp) mRNAs compared with fibroblasts. Of importance, down-regulation of Staufen1 in DM1 myoblasts rescues SG formation. Together our data show that Staufen1 participates in the inhibition of SG formation in DM1 myoblasts. These results reveal that DM1 muscle cells fail to properly respond to stress, thereby likely contributing to the complex pathogenesis of DM1.
format Online
Article
Text
id pubmed-4884064
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-48840642016-08-16 Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients Ravel-Chapuis, Aymeric Klein Gunnewiek, Amanda Bélanger, Guy Crawford Parks, Tara E. Côté, Jocelyn Jasmin, Bernard J. Mol Biol Cell Articles Myotonic dystrophy (DM1) is caused by an expansion of CUG repeats (CUG(exp)) in the DMPK mRNA 3′UTR. CUG(exp)-containing mRNAs become toxic to cells by misregulating RNA-binding proteins. Here we investigated the consequence of this RNA toxicity on the cellular stress response. We report that cell stress efficiently triggers formation of stress granules (SGs) in proliferating, quiescent, and differentiated muscle cells, as shown by the appearance of distinct cytoplasmic TIA-1– and DDX3-containing foci. We show that Staufen1 is also dynamically recruited into these granules. Moreover, we discovered that DM1 myoblasts fail to properly form SGs in response to arsenite. This blockage was not observed in DM1 fibroblasts, demonstrating a cell type–specific defect. DM1 myoblasts display increased expression and sequestration of toxic CUG(exp) mRNAs compared with fibroblasts. Of importance, down-regulation of Staufen1 in DM1 myoblasts rescues SG formation. Together our data show that Staufen1 participates in the inhibition of SG formation in DM1 myoblasts. These results reveal that DM1 muscle cells fail to properly respond to stress, thereby likely contributing to the complex pathogenesis of DM1. The American Society for Cell Biology 2016-06-01 /pmc/articles/PMC4884064/ /pubmed/27030674 http://dx.doi.org/10.1091/mbc.E15-06-0356 Text en © 2016 Ravel-Chapuis et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Ravel-Chapuis, Aymeric
Klein Gunnewiek, Amanda
Bélanger, Guy
Crawford Parks, Tara E.
Côté, Jocelyn
Jasmin, Bernard J.
Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title_full Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title_fullStr Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title_full_unstemmed Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title_short Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
title_sort staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884064/
https://www.ncbi.nlm.nih.gov/pubmed/27030674
http://dx.doi.org/10.1091/mbc.E15-06-0356
work_keys_str_mv AT ravelchapuisaymeric staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients
AT kleingunnewiekamanda staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients
AT belangerguy staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients
AT crawfordparkstarae staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients
AT cotejocelyn staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients
AT jasminbernardj staufen1impairsstressgranuleformationinskeletalmusclecellsfrommyotonicdystrophytype1patients