The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins

To maintain quality control in cells, mechanisms distinguish among improper ly folded peptides, mature and functional proteins, and proteins to be targ eted for degradation. The molecular chaperones, including heat-shock protei n Hsp90, have the ability to recognize misfolded proteins and assist in the ir conversion to a functional conformation. Disruption of Hsp90 heterocompl exes by the Hsp90 inhibitor geldanamycin leads to substrate degradation thr ough the ubiquitin-proteasome pathway(1-3), implicating this system in prot ein triage decisions. We previously identified CHIP (carboxyl terminus of H sc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). C HIP also interacts directly with a tetratricopeptide repeat acceptor site o f Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-b inding activity and transactivation potential of the glucocorticoid recepto r, a well-characterized Hsp90 substrate(5), even though it has little effec t on its synthesis. Instead, CHIP induces ubiquitylation of the glucocortic oid receptor and degradation through the proteasome. By remodelling Hsp90 h eterocomplexes to favour substrate degradation, CHIP modulates protein tria ge decisions that regulate the balance between protein folding and degradat ion for chaperone substrates.