PROLINE ISOMERASES FUNCTION DURING HEAT-SHOCK

The cyclophilins (CYPs) and FK506 binding proteins (FKBPs) are two fam ilies of distinct proline isomerases that are targets for a number of clinically important immunosuppressive drugs. Members of both families catalyze cis/trans isomerization of peptidyl-prolyl bonds, which can be a rate-limiting step during protein folding in vitro and in vivo. W e demonstrate in Saccharomyces cerevisiae that heat shock causes a 2- to 3-fold increase in the level of mRNA encoded by the major cytoplasm ic CYP gene, CYP1. The cloned CYP1 promoter confers heat-inducible exp ression upon a reporter gene, and transcriptional induction is mediate d through sequences similar to the consensus heat shock response eleme nt. Disruption of CYP1 decreases survival of cells following exposure to high temperatures, indicating that CYP1 plays a role in the stress response. A second CYP gene, CYP2, encodes a cyclophilin that is locat ed within the secretory pathway. Its expression is also stimulated by heat shock, and cells containing a disrupted CYP2 allele are more sens itive than wild-type cells to heat. By contrast, expression of the FKB 1 gene, which encodes a cytoplasmic member of the yeast FKBP family, i s neither heat responsive nor necessary for survival after exposure to heat stress.