Phosphorylation-Mediated Clearance of Amyloid-like Assemblies in Meiosis

Dev Cell. 2018 May 7;45(3):392-405.e6. doi: 10.1016/j.devcel.2018.04.001.

Abstract

Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 clearance via phosphorylation of Rim4's intrinsically disordered region. Rim4 phosphorylation leads to reversal of its amyloid-like properties and degradation by the proteasome. Our data support a model in which a threshold amount of phosphorylation, rather than modification of critical residues, is required for Rim4 clearance. Our results further demonstrate that at least some amyloid-like assemblies are not as irreversible as previously thought. We propose that the natural pathways by which cells process these structures could be deployed to act on disease-related amyloids.

Keywords: RNA-binding proteins; amyloid-like assemblies; gametogenesis; meiosis; neurodegeneration; phosphorylation; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidogenic Proteins / genetics
  • Amyloidogenic Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Meiosis / physiology*
  • Phosphorylation
  • Protein Aggregates*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Amyloidogenic Proteins
  • Intracellular Signaling Peptides and Proteins
  • Protein Aggregates
  • RNA-Binding Proteins
  • Rim4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • IME2 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases