The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies

Multiple molecular chaperones, including Hsp90 and p23, interact with membe rs of the intracellular receptor (IR) family. To investigate p23 function, we compared the effects of three p23 proteins on IR activities, yeast p23 ( sba1p) and the two human p23 homologs, p23 and tsp23. We found that Sba1p w as indistinguishable from human p23 in assays of seven IR activities in bot h animal cells and in yeast; in contrast, certain effects of tsp23 were spe cific to that homolog. Transcriptional activation by two IRs was increased by expression of any of the p23 species, whereas activation by five other I Rs was decreased by Sba1p or p23, and unaffected by tsp23. p23 was expresse d in all tissues examined except striated and cardiac muscle, whereas tsp23 accumulated in a complementary pattern; hence, p23 proteins might contribu te to tissue-specific differences in IR activities. Unlike Hsp90, which act s on IR aporeceptors to stimulate ligand potency (i.e., hormone-binding aff inity), p23 proteins acted on IR holoreceptors to alter ligand efficiencies (i.e., transcriptional activation activity). Moreover, the p23 effects dev eloped slowly, requiring prolonged exposure to hormone. In vitro, p23 inter acted preferentially with hormone-receptor-response element ternary complex es, and stimulated receptor-DNA dissociation. The dissociation was reversed by addition of a fragment of the GRIP1 coactivator, suggesting that the tw o reactions may be in competition in vivo. Our findings suggest that p23 fu nctions at one or more late steps in IR-mediated signal transduction, perha ps including receptor recycling and/or reversal of the response.