Hch1p Acts Differently From Its Homologue, Aha1p, in Regulating Sensitivity of Hsp90 to Hsp90 Inhibitors in Yeast

Hsp90 is a molecular chaperone that plays a vital role in the regulation of oncoproteins, is targeted by small molecule Hsp90-inhibitors in cancer studies, and is functionally regulated by a cohort of proteins called co-chaperones.;We determined that deletion of the co-chaperone Hch1p, but not its homologue Aha1p, restores growth in yeast expressing the temperature-sensitive Hsp90 mutants, Hsp82pA587T or Hsp82pG313S. Strains expressing either of these Hsp90 mutants are hypersensitive to Hsp90 inhibitors. Sensitivity is reversed when HCH1 is deleted. Over-expression of HCH1 confers hypersensitivity to Hsp90 inhibitors in wild-type yeast, and HCH1 deletion confers high resistance to these drugs. We also determined that Hch1p, but not Aha1p, is essential for growth of yeast expressing the temperature-sensitive mutant, Hsp82pE381K . We conclude that the co-chaperone Hch1p plays an important role in regulating sensitivity to drugs that inhibit Hsp90 and regulates Hsp90 in a manner distinct from its homologue, Aha1p.