Article

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

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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.

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Acknowledgements

We thank S. Alberti (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany), M. Ralser (Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK) and K. Weis (Institute of Biochemistry, Department of Biology, ETH Zürich, Zürich, Switzerland) for providing reagents; S. McKnight, D. Frantz and L. Berchowitz for help with b-isox experiments; A. Timofiiva for help with microscopy; and T. Mayor, A. Smith, P. Kimmig and members of the Peter laboratory for helpful discussions and comments on the manuscript. This work was funded by the Swiss National Science Foundation (SNF, project grants 31003A_166513 to R.D. and 310030B_160312 to M.P.), the European Research Council (ERC, Rubinet) and ETH Zürich.

Author information

Author notes

    • Yuehan Feng

    Present address: Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA.

Affiliations

  1. Institute of Biochemistry, Department of Biology, ETH Zürich, Otto-Stern-Weg 3, 8093 Zürich, Switzerland

    • Shady Saad
    • , Gea Cereghetti
    • , Yuehan Feng
    • , Paola Picotti
    • , Matthias Peter
    •  & Reinhard Dechant
  2. Life Science Zürich, PhD Program for Molecular and Translational Biomedicine, CH-8044 Zürich, Switzerland

    • Shady Saad
  3. Life Science Zürich, PhD Program for Molecular Life Sciences, 8057 Zürich, Switzerland

    • Gea Cereghetti
    •  & Yuehan Feng

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Contributions

Conceptualization: S.S., M.P. and R.D.; investigation: S.S., G.C. and Y.F.; formal analysis: R.D.; writing—original draft preparation: S.S. and R.D.; writing—review and editing: S.S., G.C., Y.F., P.P., M.P. and R.D.; visualization: S.S. and R.D.; supervision: P.P., M.P. and R.D.; funding acquisition: M.P. and R.D.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Matthias Peter or Reinhard Dechant.

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