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

• DOI: 10.1016/j.molcel.2021.12.031
• Publication Date: 2022-01-20T15:27:59Z
• Authors: Maximilian M. Biebl; Florent Delhommel; Ofrah Faust; Krzysztof M. Zak; Ganesh Agam; Xiaoyan Guo; Moritz Mühlhofer; Vinay Dahiya; Daniela Hillebrand; Grzegorz M. Popowicz; Martin Kampmann; Don C. Lamb; Rina Rosenzweig; Michael Sattler; Johannes Buchner
• Keywords: Protein Folding; 0303 health sciences; Binding Sites; Cell Survival; Nuclear Proteins; Cell Cycle Proteins; HSP40 Heat-Shock Proteins; ddc:; Co-chaperones ; Glucocorticoid Receptor ; Hsp40 ; Hsp70 ; Hsp90 ; Molecular Chaperones ; Nmr Spectroscopy ; Nudc ; Protein Folding ; Spfret; Molecular Docking Simulation; Kinetics; 03 medical and health sciences; HEK293 Cells; Receptors, Glucocorticoid; Humans; Protein Interaction Domains and Motifs; HSP90 Heat-Shock Proteins; Tumor Suppressor Protein p53; K562 Cells; Protein Binding

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.