hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation
Summary: Prion-like proteins form multivalent assemblies and phase separate into membraneless organelles. Heterogeneous ribonucleoprotein D-like (hnRNPDL) is a RNA-processing prion-like protein with three alternative splicing (AS) isoforms, which lack none, one, or both of its two disordered domains...
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doaj-cc5833f6bb294484ba448e739b6c1e9f2020-11-24T21:24:05ZengElsevierCell Reports2211-12472020-01-0130411171128.e5hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its AggregationCristina Batlle0Peiguo Yang1Maura Coughlin2James Messing3Mireia Pesarrodona4Elzbieta Szulc5Xavier Salvatella6Hong Joo Kim7J. Paul Taylor8Salvador Ventura9Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra 08193, SpainDepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 201815, USAInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Joint BSC-IRB Research Programme in Computational Biology, Baldiri Reixac 10, 08028 Barcelona, Spain; ICREA, Passeig Lluís Companys 23, 08010 Barcelona, SpainDepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 201815, USA; Corresponding authorInstitut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra 08193, Spain; Corresponding authorSummary: Prion-like proteins form multivalent assemblies and phase separate into membraneless organelles. Heterogeneous ribonucleoprotein D-like (hnRNPDL) is a RNA-processing prion-like protein with three alternative splicing (AS) isoforms, which lack none, one, or both of its two disordered domains. It has been suggested that AS might regulate the assembly properties of RNA-processing proteins by controlling the incorporation of multivalent disordered regions in the isoforms. This, in turn, would modulate their activity in the downstream splicing program. Here, we demonstrate that AS controls the phase separation of hnRNPDL, as well as the size and dynamics of its nuclear complexes, its nucleus-cytoplasm shuttling, and amyloidogenicity. Mutation of the highly conserved D378 in the disordered C-terminal prion-like domain of hnRNPDL causes limb-girdle muscular dystrophy 1G. We show that D378H/N disease mutations impact hnRNPDL assembly properties, accelerating aggregation and dramatically reducing the protein solubility in the muscle of Drosophila, suggesting a genetic loss-of-function mechanism for this muscular disorder. : Batlle et al. show that alternative splicing controls heterogeneous ribonucleoprotein D-like (hnRNPDL) phase separation, aggregation, and solubility. Mutations that cause LGMD1G accelerate hnRNPDL aggregation and promote insolubility in Drosophila. Keywords: hnRNPDL, alternative splicing, isoforms, phase separation, aggregation, amyloid, prion-like, disease, mutation, LGMD1Ghttp://www.sciencedirect.com/science/article/pii/S2211124719317450 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cristina Batlle Peiguo Yang Maura Coughlin James Messing Mireia Pesarrodona Elzbieta Szulc Xavier Salvatella Hong Joo Kim J. Paul Taylor Salvador Ventura |
spellingShingle |
Cristina Batlle Peiguo Yang Maura Coughlin James Messing Mireia Pesarrodona Elzbieta Szulc Xavier Salvatella Hong Joo Kim J. Paul Taylor Salvador Ventura hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation Cell Reports |
author_facet |
Cristina Batlle Peiguo Yang Maura Coughlin James Messing Mireia Pesarrodona Elzbieta Szulc Xavier Salvatella Hong Joo Kim J. Paul Taylor Salvador Ventura |
author_sort |
Cristina Batlle |
title |
hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation |
title_short |
hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation |
title_full |
hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation |
title_fullStr |
hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation |
title_full_unstemmed |
hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation |
title_sort |
hnrnpdl phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2020-01-01 |
description |
Summary: Prion-like proteins form multivalent assemblies and phase separate into membraneless organelles. Heterogeneous ribonucleoprotein D-like (hnRNPDL) is a RNA-processing prion-like protein with three alternative splicing (AS) isoforms, which lack none, one, or both of its two disordered domains. It has been suggested that AS might regulate the assembly properties of RNA-processing proteins by controlling the incorporation of multivalent disordered regions in the isoforms. This, in turn, would modulate their activity in the downstream splicing program. Here, we demonstrate that AS controls the phase separation of hnRNPDL, as well as the size and dynamics of its nuclear complexes, its nucleus-cytoplasm shuttling, and amyloidogenicity. Mutation of the highly conserved D378 in the disordered C-terminal prion-like domain of hnRNPDL causes limb-girdle muscular dystrophy 1G. We show that D378H/N disease mutations impact hnRNPDL assembly properties, accelerating aggregation and dramatically reducing the protein solubility in the muscle of Drosophila, suggesting a genetic loss-of-function mechanism for this muscular disorder. : Batlle et al. show that alternative splicing controls heterogeneous ribonucleoprotein D-like (hnRNPDL) phase separation, aggregation, and solubility. Mutations that cause LGMD1G accelerate hnRNPDL aggregation and promote insolubility in Drosophila. Keywords: hnRNPDL, alternative splicing, isoforms, phase separation, aggregation, amyloid, prion-like, disease, mutation, LGMD1G |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719317450 |
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