Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51

Squirrel monkeys are neotropical primates that have high circulating cortis ol to compensate for expression of glucocorticoid receptors (GRs) with redu ced affinity. The low binding affinity of squirrel monkey GR does not resul t from substitutions in the receptor, because squirrel monkey GR expressed in vitro exhibits high affinity. Rather, squirrel monkeys express a soluble factor that, in mixing studies of cytosol from squirrel monkey lymphocytes (SML) and mouse L929 cells, reduced GR binding affinity by 11-fold. In an effort to identify this factor, the cellular levels of components of the GR heterocomplex in SML and human lymphocytes (HL) were compared. The immunop hilin FKBP51 was 13-fold higher in SML than in HL cytosol; FKBP52 in SML wa s 42% of that in HL cytosol. A role for changes in immunophilins, causing g lucocorticoid resistance in neotropical primates, is supported by the follo wing: the changes in FKBP51 and FKBP52 were observed in cells from other ne otropical primates with glucocorticoid resistance; the elevated level of FK BP51 was reflected in an abundance of FKBP51 in heat shock protein 90 compl exes in SML; when cytosols of SML and L929 cells were mixed, the decrease i n GR binding was associated with incorporation of FKBP51 into GR heterocomp lexes; the effect of SML cytosol on GR binding was reproduced with cytosol from COS cells expressing squirrel monkey FKBP51; and both the effect of SM L cytosol on GR binding and the incorporation of FKBP51 into GR heterocompl exes were blocked by FK506. Regulation of GR binding by FKB51 represents a previously unrecognized mechanism for regulating glucocorticoid sensitivity .