Human FKBP5 Negatively Regulates Transcription through Inhibition of P-TEFb Complex Formation

Although a large number of recent studies indicate strong association of FKBP5 (aka FKBP51) functions with various stress-related psychiatric disorders, the overall mechanisms are poorly understood. Beyond a few studies indicating its functions in regulating glucocorticoid receptor, and AKT signaling pathways, other functional roles (if any) are unclear. Here, we report an antiproliferative role of human FKBP5 through negative regulation of expression of proliferation-related genes. Mechanistically, we show that, owing to the same region of interaction on cyclin-dependent kinse 9 (CDK9), human FKBP5 directly competes with cyclin T1 for functional positive transcription elongation factor b (P-TEFb) complex formation. In vitro biochemical assays, coupled with cell-based assays, showed a strong negative effect of FKBP5 on P-TEFb-mediated phosphorylation of diverse substrates. Consistently, FKBP5 knockdown showed enhanced P-TEFb complex formation that led to increased global RNA polymerase II C-terminal domain (CTD) phosphorylation, expression of proliferation-related genes, and subsequent proliferation. Thus, our results show an important role for FKBP5 in negative regulation of P-TEFb functions within mammalian cells.