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

Dmitri Segal, Stefan Maier, Giovanni J. Mastromarco, Wesley Wei Qian, Syed Nabeel-Shah, Hyunmin Lee, Gaelen Moore, Jessica Lacoste, Brett Larsen, Zhen Yuan Lin, Abeeshan Selvabaskaran, Karen Liu, Craig Smibert, Zhaolei Zhang, Jack Greenblatt, Jian Peng, Hyun O. Lee, Anne Claude Gingras, Mikko Taipale

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)974-993.e15
JournalMolecular cell
Volume83
Issue number6
DOIs
StatePublished - Mar 16 2023
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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