title: Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.
abstract: Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amandine
authors.initials: A
authors.lastname: Molliex
authors.affiliation: Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Temirov
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jihun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Coughlin
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Anderson P
authors.initials: AP
authors.lastname: Kanagaraj
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hong Joo
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: tanja.mittag@stjude.org.
authors.forename: Tanja
authors.initials: T
authors.lastname: Mittag
authors.affiliation: Howard Hughes Medical Institute, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: jpaul.taylor@stjude.org.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
mesh_terms: D000682:Amyloid / Q000378:metabolism; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000378:metabolism*
chemical_list: D000682:Amyloid; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000598624:TARDBP protein, human; C000619656:hnRNPA1 protein, human