NudC guides client transfer between the Hsp40/70 and Hsp90 chaperone systems

Mol Cell. 2022 Feb 3;82(3):555-569.e7. doi: 10.1016/j.molcel.2021.12.031. Epub 2022 Jan 20.


In the eukaryotic cytosol, the Hsp70 and the Hsp90 chaperone machines work in tandem with the maturation of a diverse array of client proteins. The transfer of nonnative clients between these systems is essential to the chaperoning process, but how it is regulated is still not clear. We discovered that NudC is an essential transfer factor with an unprecedented mode of action: NudC interacts with Hsp40 in Hsp40-Hsp70-client complexes and displaces Hsp70. Then, the interaction of NudC with Hsp90 allows the direct transfer of Hsp40-bound clients to Hsp90 for further processing. Consistent with this mechanism, NudC increases client activation in vitro as well as in cells and is essential for cellular viability. Together, our results show the complexity of the cooperation between the major chaperone machineries in the eukaryotic cytosol.

Keywords: Glucocorticoid receptor; Hsp40; Hsp70; Hsp90; NMR spectroscopy; NudC; co-chaperones; molecular chaperones; protein folding; spFRET.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Survival
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics
  • HSP40 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • K562 Cells
  • Kinetics
  • Molecular Docking Simulation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Cell Cycle Proteins
  • DNAJB1 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • NUDC protein, human
  • Nuclear Proteins
  • Receptors, Glucocorticoid
  • TP53 protein, human
  • Tumor Suppressor Protein p53