hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation
hnRNPDL isoforms behavior is governed by the presence of two, one or none disordered regions resulting in phase separation, aggregation or solubility, respectively. LGMD1G disease causing mutations in hnRNPDL accelerate the aggregation process and the protein becomes completely insoluble in a Drosophila disease model.
Batlle C, Yang P, Coughlin M, Messing J, Pesarrodona M, Szulc E, Salvatella X, Kim HJ, Taylor JP, Ventura S.
Cell Rep 2020 Jan; 30: 1117.
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.
PubMed: 31995753. Doi: 10.1016/j.celrep.2019.12.080. OPEN Free PMC
