The hsp90-FKBP52 Complex Regulates Nuclear Translocation of hTERT and Telomerase Activity

Telomerase is a unique ribonucleoprotein enzyme that is required for continued cell proliferation. To generate catalytically active telomerase, hTERT should be transported to the nucleus and assembled with the telomerase RNA component. The molecular chaperones Hsp90 and p23 have been shown to maintain hTERT in a conformation enabling nuclear translocation. However, the regulatory role of chaperones in nuclear transport of hTERT remains unclear. In this work, we demonstrate that immunophilin FKBP52 links the hTERT-Hsp90 complex to dynein/dynactin motor, thereby promoting the cytoplasmic transport of hTERT to the nucleus along microtubule tracks. FKBP52 interacts with the hTERT-Hsp90 complex through the TPR domain binding to Hsp90 as well as with the dynamitin component of the dynein-associated dynactin complex through the PPIase domain. Depletion of FKBP52 inhibits nuclear transport of hTERT and results in a cytoplasmic accumulation. The resulting cytoplasmic hTERT is rapidly degraded through ubiquitin-dependent proteolysis, thereby abrogating telomerase activity. In addition, overexpression of dynamitin, which is known to dissociate dynein/dynactin motor from its cargoes, reduced telomerase activity. These results provide a molecular mechanism by which FKBP52 modulates telomerase activity by regulating nuclear transport of hTERT.