Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress

Nat Cell Biol. 2017 Oct;19(10):1202-1213. doi: 10.1038/ncb3600. Epub 2017 Aug 28.

Abstract

Protein aggregation is mostly viewed as deleterious and irreversible causing several pathologies. However, reversible protein aggregation has recently emerged as a novel concept for cellular regulation. Here, we characterize stress-induced, reversible aggregation of yeast pyruvate kinase, Cdc19. Aggregation of Cdc19 is regulated by oligomerization and binding to allosteric regulators. We identify a region of low compositional complexity (LCR) within Cdc19 as necessary and sufficient for reversible aggregation. During exponential growth, shielding the LCR within tetrameric Cdc19 or phosphorylation of the LCR prevents unscheduled aggregation, while its dephosphorylation is necessary for reversible aggregation during stress. Cdc19 aggregation triggers its localization to stress granules and modulates their formation and dissolution. Reversible aggregation protects Cdc19 from stress-induced degradation, thereby allowing cell cycle restart after stress. Several other enzymes necessary for G1 progression also contain LCRs and aggregate reversibly during stress, implying that reversible aggregation represents a conserved mechanism regulating cell growth and survival.

MeSH terms

  • Cell Cycle Proteins / chemical synthesis
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle*
  • Cell Proliferation*
  • Mutation
  • Phosphorylation
  • Protein Aggregates*
  • Protein Conformation
  • Proteolysis
  • Pyruvate Kinase / chemical synthesis
  • Pyruvate Kinase / chemistry
  • Pyruvate Kinase / metabolism*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae Proteins / chemical synthesis
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Stress, Physiological*
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Cell Cycle Proteins
  • Protein Aggregates
  • Saccharomyces cerevisiae Proteins
  • Cdc19 protein, S cerevisiae
  • Pyruvate Kinase