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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2016
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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 |
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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 |
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