Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization

Cell. 2015 Sep 24;163(1):123-33. doi: 10.1016/j.cell.2015.09.015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism
  • Cell Line, Tumor
  • Cytoplasmic Granules / chemistry*
  • Cytoplasmic Granules / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / chemistry
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Protein Aggregation, Pathological / metabolism*

Substances

  • Amyloid
  • DNA-Binding Proteins
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • TDP-43 protein, human
  • hnRNPA1 protein, human