title: Hsp90-binding immunophilin FKBP52 modulates telomerase activity by promoting the cytoplasmic retrotransport of hTERT.
abstract: Telomerase is a unique ribonucleoprotein enzyme that is required for continued cell proliferation. To generate catalytically active telomerase, human telomerase reverse transcriptase (hTERT) must translocate to the nucleus and assemble with the RNA component of telomerase. The molecular chaperones heat shock protein 90 (Hsp90) and p23 maintain hTERT in a conformation that enables nuclear translocation. However, the regulatory role of chaperones in nuclear transport of hTERT remains unclear. In this work, we demonstrate that immunophilin FK506-binding protein (FKBP)52 linked the hTERT-Hsp90 complex to the dynein-dynactin motor, thereby promoting the transport of hTERT to the nucleus along microtubules. FKBP52 interacted with the hTERT-Hsp90 complex through binding of the tetratricopeptide repeat domain to Hsp90 and binding of the dynamitin (Dyt) component of the dynein-associated dynactin complex to the peptidyl prolyl isomerase domain. The depletion of FKBP52 inhibited nuclear transport of hTERT, resulting in cytoplasmic accumulation. Cytoplasmic hTERT was rapidly degraded through ubiquitin (Ub)-dependent proteolysis, thereby abrogating telomerase activity. In addition, overexpression of dynamitin, which is known to dissociate the dynein-dynactin motor from its cargoes, reduced telomerase activity. Collectively, these results provide a molecular mechanism by which FKBP52 modulates telomerase activity by promoting dynein-dynactin-dependent nuclear import of hTERT.
authors: Department of Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
authors: Yu Young
authors: YY
authors: Jeong
authors: Department of Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
authors: Joonyoung
authors: J
authors: Her
authors: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors: Sue-Young
authors: SY
authors: Oh
authors: Department of Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors: In Kwon
authors: IK
authors: Chung
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C509186:TERT protein, human; D019098:Telomerase; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D000071876:Prostaglandin-E Synthases
keywords: FKBP52; Hsp90; dynein/dynactin motor; hTERT; nuclear transport; telomerase