A central chaperone-like role for 14-3-3 proteins in human cells

Mol Cell. 2023 Mar 16;83(6):974-993.e15. doi: 10.1016/j.molcel.2023.02.018.


14-3-3 proteins are highly conserved regulatory proteins that interact with hundreds of structurally diverse clients and act as central hubs of signaling networks. However, how 14-3-3 paralogs differ in specificity and how they regulate client protein function are not known for most clients. Here, we map the interactomes of all human 14-3-3 paralogs and systematically characterize the effect of disrupting these interactions on client localization. The loss of 14-3-3 binding leads to the coalescence of a large fraction of clients into discrete foci in a client-specific manner, suggesting a central chaperone-like function for 14-3-3 proteins. Congruently, the engraftment of 14-3-3 binding motifs to nonclients can suppress their aggregation or phase separation. Finally, we show that 14-3-3s negatively regulate the localization of the RNA-binding protein SAMD4A to cytoplasmic granules and inhibit its activity as a translational repressor. Our work suggests that 14-3-3s have a more prominent role as chaperone-like molecules than previously thought.

Keywords: 14-3-3 proteins; affinity purification; aggregation; chaperones; functional proteomics; mass spectrometry; phase transitions; protein quality control; proximity-dependent biotinylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins* / genetics
  • 14-3-3 Proteins* / metabolism
  • HSP90 Heat-Shock Proteins* / metabolism
  • Humans
  • Molecular Chaperones / metabolism
  • Protein Binding


  • 14-3-3 Proteins
  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones