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hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation
Batlle Carreras, Cristina (Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Yang, Peiguo (St. Jude Children's Research Hospital. Department of Cell and Molecular Biology)
Coughlin, Maura (St. Jude Children's Research Hospital. Department of Cell and Molecular Biology)
Messing, James (Howard Hughes Medical Institute)
Pesarrodona Roches, Mireia (Institut de Recerca Biomèdica)
Szulc, Elzbieta (Institut de Recerca Biomèdica)
Salvatella, Xavier (Institut de Recerca Biomèdica)
Kim, Hong Joo (St. Jude Children's Research Hospital. Department of Cell and Molecular Biology)
Taylor, J. Paul (Howard Hughes Medical Institute)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date: 2020
Abstract: 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.
Note: Altres ajuts: .V. acknowledges funding from ICREA (ICREA-Academia 2016). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (government of Spain). C.B. acknowledges funding from "Ministerio de Educación y Formación Profesional
Note: Número d'acord de subvenció EC/H2020/648201
Note: Número d'acord de subvenció MINECO/BIO2016-78310-R
Note: Número d'acord de subvenció MINECO/BIO2015-70092-R
Note: Número d'acord de subvenció MINECO/BIO2012-31043
Note: Número d'acord de subvenció AGAUR/2017/SGR-324
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. Creative Commons
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: Hnrnpdl ; Alternative splicing ; Isoforms ; Phase separation ; Aggregation ; Amyloid ; Prion-like ; Disease ; Mutation ; LGMD1G
Published in: Cell reports, Vol. 30, issue 4 (Jan. 2020) , p. 1117-1128, ISSN 2211-1247

DOI: 10.1016/j.celrep.2019.12.080
PMID: 31995753

18 p, 3.6 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles

 Record created 2020-06-22, last modified 2020-08-02

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