Human FKBP5 negatively regulates transcription through inhibition of P-TEFb complex formation.

Although large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorder, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor-, and AKT-signalling pathways, other functional roles (if any) are unclear. In this study, we report an anti-proliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. Mechanistically, we show that, owing to same region of interaction on CDK9, human FKBP5 directly competes with CyclinT1 for functional P-TEFb complex formation. In vitro biochemical coupled with cell-based assays, showed strong negative effect of FKBP5 on P-TEFb-mediated phosphorylation of diverse substrates. Consistently, FKBP5 knockdown showed enhanced P-TEFb complex formation leading to increased global RNA polymerase II CTD phosphorylation and expression of proliferation-related genes and subsequent proliferation. Thus, our results show an important role of FKBP5 in negative regulation of P-TEFb functions within mammalian cells.