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The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization

The RBP associated with lethal yellow mutation (RALY) is a member of the heterogeneous nuclear ribonucleoprotein family whose transcriptome and interactome have been recently characterized. RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of s...

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Autores principales: Gasperini, Lisa, Rossi, Annalisa, Cornella, Nicola, Peroni, Daniele, Zuccotti, Paola, Potrich, Valentina, Quattrone, Alessandro, Macchi, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340211/
https://www.ncbi.nlm.nih.gov/pubmed/30354839
http://dx.doi.org/10.1091/mbc.E18-02-0108
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author Gasperini, Lisa
Rossi, Annalisa
Cornella, Nicola
Peroni, Daniele
Zuccotti, Paola
Potrich, Valentina
Quattrone, Alessandro
Macchi, Paolo
author_facet Gasperini, Lisa
Rossi, Annalisa
Cornella, Nicola
Peroni, Daniele
Zuccotti, Paola
Potrich, Valentina
Quattrone, Alessandro
Macchi, Paolo
author_sort Gasperini, Lisa
collection PubMed
description The RBP associated with lethal yellow mutation (RALY) is a member of the heterogeneous nuclear ribonucleoprotein family whose transcriptome and interactome have been recently characterized. RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression. PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. Confirming that inhibiting FUS methylation increases its nuclear import, we report that RALY knockout enhances FUS NLS mutants’ nuclear translocation, hence decreasing aggregate formation. Furthermore, we characterize the RNA-dependent interaction of RALY with FUS in motor neurons. We show that mutations in FUS NLS as well as in RALY NLS reciprocally alter their localization and interaction with target mRNAs. These data indicate that RALY’s activity is impaired in FUS pathology models, raising the possibility that RALY might modulate disease onset and/or progression.
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spelling pubmed-63402112019-03-02 The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization Gasperini, Lisa Rossi, Annalisa Cornella, Nicola Peroni, Daniele Zuccotti, Paola Potrich, Valentina Quattrone, Alessandro Macchi, Paolo Mol Biol Cell Articles The RBP associated with lethal yellow mutation (RALY) is a member of the heterogeneous nuclear ribonucleoprotein family whose transcriptome and interactome have been recently characterized. RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression. PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. Confirming that inhibiting FUS methylation increases its nuclear import, we report that RALY knockout enhances FUS NLS mutants’ nuclear translocation, hence decreasing aggregate formation. Furthermore, we characterize the RNA-dependent interaction of RALY with FUS in motor neurons. We show that mutations in FUS NLS as well as in RALY NLS reciprocally alter their localization and interaction with target mRNAs. These data indicate that RALY’s activity is impaired in FUS pathology models, raising the possibility that RALY might modulate disease onset and/or progression. The American Society for Cell Biology 2018-12-15 /pmc/articles/PMC6340211/ /pubmed/30354839 http://dx.doi.org/10.1091/mbc.E18-02-0108 Text en © 2018 Gasperini, Rossi, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 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.
spellingShingle Articles
Gasperini, Lisa
Rossi, Annalisa
Cornella, Nicola
Peroni, Daniele
Zuccotti, Paola
Potrich, Valentina
Quattrone, Alessandro
Macchi, Paolo
The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title_full The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title_fullStr The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title_full_unstemmed The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title_short The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization
title_sort hnrnp raly regulates prmt1 expression and interacts with the als-linked protein fus: implication for reciprocal cellular localization
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340211/
https://www.ncbi.nlm.nih.gov/pubmed/30354839
http://dx.doi.org/10.1091/mbc.E18-02-0108
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