Hsp27 chaperones FUS phase separation under the modulation of stress-induced phosphorylation

Nat Struct Mol Biol. 2020 Apr;27(4):363-372. doi: 10.1038/s41594-020-0399-3. Epub 2020 Mar 30.

Abstract

Protein phase separation drives the assembly of membraneless organelles, but little is known about how these membraneless organelles are maintained in a metastable liquid- or gel-like phase rather than proceeding to solid aggregation. Here, we find that human small heat-shock protein 27 (Hsp27), a canonical chaperone that localizes to stress granules (SGs), prevents FUS from undergoing liquid-liquid phase separation (LLPS) via weak interactions with the FUS low complexity (LC) domain. Remarkably, stress-induced phosphorylation of Hsp27 alters its activity, leading Hsp27 to partition with FUS LC to preserve the liquid phase against amyloid fibril formation. NMR spectroscopy demonstrates that Hsp27 uses distinct structural mechanisms for both functions. Our work reveals a fine-tuned regulation of Hsp27 for chaperoning FUS into either a polydispersed state or a LLPS state and suggests an essential role for Hsp27 in stabilizing the dynamic phase of stress granules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP27 Heat-Shock Proteins / chemistry*
  • HSP27 Heat-Shock Proteins / genetics
  • HSP27 Heat-Shock Proteins / isolation & purification
  • Humans
  • Liquid-Liquid Extraction
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / isolation & purification
  • Phosphorylation
  • Protein Binding / genetics
  • Protein Domains / genetics
  • RNA-Binding Protein FUS / chemistry*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / isolation & purification
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • Stress, Physiological / genetics

Substances

  • FUS protein, human
  • HSP27 Heat-Shock Proteins
  • Molecular Chaperones
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins