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.

Dmitri Segal ¹, Stefan Maier ², Giovanni J Mastromarco ³, Wesley Wei Qian ⁴, Syed Nabeel-Shah ¹, Hyunmin Lee ⁵, Gaelen Moore ³, Jessica Lacoste ¹, Brett Larsen ², Zhen-Yuan Lin ², Abeeshan Selvabaskaran ⁶, Karen Liu ⁶, Craig Smibert ⁷, Zhaolei Zhang ⁸, Jack Greenblatt ¹, Jian Peng ⁴, Hyun O Lee ³, Anne-Claude Gingras ⁹, Mikko Taipale ¹⁰

Affiliations

1 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
2 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada.
3 Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
4 Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
5 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
6 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
7 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
8 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5S 3G4, Canada.
9 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada. Electronic address: gingras@lunenfeld.ca.
10 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: mikko.taipale@utoronto.ca.

PMID: 36931259 DOI: 10.1016/j.molcel.2023.02.018

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.

Keywords

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

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