Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52.

Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to the regulation of the biological functions of several client-proteins. Among these Hsp90-binding immunophilins, there are two highly homologous members named FKBP51 and FKBP52 (FK506-binding protein of 51-kDa and 52-kDa, respectively) that were first characterized as components of the Hsp90-based heterocomplex associated to steroid receptors.

Regulation of NF-κB signalling cascade by immunophilins.

The fine regulation of signalling cascades is a key event required to maintain the appropriate functional properties of a cell when a given stimulus triggers specific biological responses. In this sense, cumulative experimental evidence during the last years has shown that high molecular weight immunophilins possess a fundamental importance in the regulation of many of these processes. It was first discovered that TPR-domain immunophilins such as FKBP51 and FKBP52 play a cardinal role, usually in an antagonistic fashion, in the regulation of several members of the steroid receptor family via its interaction with the heat-shock protein of 90-kDa, Hsp90.

NF-κB transcriptional activity is modulated by FK506-binding proteins FKBP51 and FKBP52: a role for peptidyl-prolyl isomerase activity.

Hsp90 binding immunophilins FKBP51 and FKBP52 modulate steroid receptor trafficking and hormone-dependent biological responses. With the purpose to expand this model to other nuclear factors that are also subject to nuclear-cytoplasmic shuttling, we analyzed whether these immunophilins modulate NF-κB signaling. It is demonstrated that FKBP51 impairs both the nuclear translocation rate of NF-κB and its transcriptional activity.