Hsp90 co-chaperone FKBP4 facilitates CCT8 folding and connects Hsp90 to chaperonin-dependent proteostasis.

Hsp70, Hsp90, and chaperonin complexes are three essential molecular chaperones facilitating protein folding within eukaryotic cells. However, the important interplay among these systems is incompletely understood. FKBP4 is a co-chaperone of Hsp90 and exhibits increased expression in multiple cancer types. In this study, we employed two proximity-dependent biotin identification (BioID) systems to explore potential clients of the FKBP4-Hsp90 complex. Analysis of BioID mass spectrometry data revealed that the top category of the FKBP4-associated protein is cadherin-binding proteins, and one of the cadherin-binding proteins is a subunit of the chaperonin containing TCP-1 complex, CCT8. Furthermore, knockdown of FKBP4 led to CCT8 aggregation and compromised the stability of its clients, CDK2 and α-tubulin, indicating the dependency of the FKBP4-Hsp90 complex on CCT8 folding. These findings suggest that CCT8 is a client of the FKBP4-Hsp90 complex, implying a functional crosstalk between two of the three protein folding systems in eukaryotic cells.