Immunophilins, Refsum disease, and lupus nephritis: The peroxisomal enzymephytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein

FKBP52 (FKBP59, FKBP4) is a "macro" immunophilin that, although sharing hig h structural and functional homologies in its amino-terminal domain with FK BP12 (FKBP1), does not have immunosuppressant activity when complexed with FK506, unlike FKBP12. To investigate the physiological function of FKBP52, we used the yeast two-hybrid system as an approach to find its potential pr otein partners and, from that, its cellular role. This methodology, which a lready has allowed us to find the FK506-binding protein (FKBP)-associated p rotein FAP48, also led to the detection of another FKBP-associated protein. Determination of the sequence of this protein permitted its identification as phytanoyl-CoA alpha-hydroxylase (PAHX), a peroxisomal enzyme that so fa r was unknown as an FKBP-associated protein. Inactivation of this enzyme is responsible for Refsum disease in humans. The protein also corresponds to the mouse protein LN1, which could be involved in the progress of lupus nep hritis. We show here that PAHX has the physical capacity to interact with t he FKBP12-like domain of FKBP52, but not with FKBP12, suggesting that it is a particular and specific target of FKBP52. Whereas the binding of calcine urin to FKBP12 is potentiated by FK506, the specific association of PAHX an d FKBP52 is maintained in the presence of FK506. This observation suggests that PAHX is a serious candidate for studying the cellular signaling pathwa y(s) involving FKBP52 in the presence of immunosuppressant drugs.