hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation.
Por:
Batlle C, Yang P, Coughlin M, Messing J, Pesarrodona M, Szulc E, Salvatella X, Kim HJ, Taylor JP and Ventura S
Publicada:
28 ene 2020
Categoría:
Biochemistry, genetics and molecular biology (miscellaneous)
Resumen:
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.
Filiaciones:
:
Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra 08193, Spain
Yang P:
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Coughlin M:
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Messing J:
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Howard Hughes Medical Institute, Chevy Chase, MD 201815, USA
Pesarrodona M:
Institute 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
Szulc E:
Institute 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
Salvatella X:
Institute 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 Lluis Companys 23, 08010 Barcelona, Spain
Kim HJ:
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Taylor JP:
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Howard Hughes Medical Institute, Chevy Chase, MD 201815, USA
Ventura S:
Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autónoma de Barcelona, Bellaterra 08193, Spain. Electronic address:
Green Published, gold
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