A specialized HSP90 co-chaperone network regulates steroid hormone receptor response to ligand

Abstract

Heat shock protein-90 (Hsp90) is an essential molecular chaperone responsible for the stability and activation of over 300 client proteins, many of which have been implicated in tumorigenesis. The chaperone function of Hsp90 is dependent on its ability to hydrolyze ATP. The ATP hydrolysis cycle, and therefore chaperone activity, is tightly regulated by a group of proteins known as co-chaperones and post-translational modifications. Folliculin-interacting proteins 1 and 2 (FNIP1 and FNIP2) are recently recognized Hsp90 co-chaperones with 74% amino acid sequence homology and largely overlapping reported functions. Another recently identified co-chaperone with similar functionality is the tumor suppressor Tsc1. FNIPs and Tsc1 co-chaperone activities have been characterized, however there remains a gap in understanding the functional differences between FNIP1, FNIP2 and Tsc1. Here, we dissected the impact of these newly identified co-chaperones towards Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1 and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. We further demonstrate that FNIP1 and Tsc1 interact with a large set of overlapping proteins, whereas FNIP2 interactors are predominantly unique. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations. The results presented here demonstrate physiological and mechanistic differences between the co-chaperones FNIP1, FNIP2 and Tsc1.