Abstract
FK506-binding proteins are members of the immunophilin family of proteins. Those immunophilins associated to the 90-kDa-heat-shock protein, Hsp90, have been proposed as potential modulators of signalling cascade factors chaperoned by Hsp90. FKBP51 and FKBP52 are the best characterized Hsp90-bound immunophilins first described associated to steroid-receptors. The reverse transcriptase subunit of telomerase, hTERT, is also an Hsp90 client-protein and is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division. Because FKBP51 is also a highly expressed protein in cancer tissues, we analyzed its potential association with hTERT·Hsp90 complexes and its possible biological role. In this study it is demonstrated that both immunophilins, FKBP51 and FKBP52, co-immunoprecipitate with hTERT. The Hsp90 inhibitor radicicol disrupts the heterocomplex and favors the partial cytoplasmic relocalization of hTERT in similar manner as the overexpression of the TPR-domain peptide of the immunophilin. While confocal microscopy images show that FKBP51 is primarily localized in mitochondria and hTERT is totally nuclear, upon the onset of oxidative stress, FKBP51 (but not FKBP52) becomes mostly nuclear colocalizing with hTERT, and longer exposure times to peroxide favors hTERT export to mitochondria. Importantly, telomerase activity of hTERT is significantly enhanced by FKBP51. These observations support the emerging role assigned to FKBP51 as antiapoptotic factor in cancer development and progression, and describe for the first time the potential role of this immunophilin favoring the clonal expansion by enhancing telomerase activity.
Highlights
Immunophilins belong to a family of proteins that exhibit high specificity in binding immunosuppressive agents
Inasmuch as telomerase activity is significantly increased in those cell types where FK506-binding protein of 51-kDa (FKBP51) is highly expressed, and because both proteins are heat-shock protein of 90-kDa (Hsp90)-interacting proteins, in this study we explored whether this tetratricopeptide-repeat motif (TPR)-domain immunophilin forms complexes with human reverse transcriptase subunit of telomerase (hTERT) and its potential role in the regulation of telomerase activity
This study demonstrates the association of the Hsp90-binding immunophilin FKBP51 with hTERT
Summary
Immunophilins belong to a family of proteins that exhibit high specificity in binding immunosuppressive agents. The signature domain of this family is the PPIase (peptidyl-prolyl-(cis/ trans)-isomerase) domain (Erlejman et al, 2013; Guy et al, 2015; Storer et al, 2011), where immunosuppressive drugs bind and inhibit the intrinsic PPIase activity of these proteins. The low molecular weight immunophilins FKBP12 (12-kDa) and CyPA (17kDa) are responsible for the immunosuppressive action by inhibition of the Ser/Thr-phosphatase activity of PP2B/calcineurin in lymphocytes (Ho et al, 1996). In addition to the PPIase domain, high molecular weight immunophilins show other domains such as the tetratricopeptide-repeat motif (TPR), through which they bind to Hsp (Storer et al, 2011). The biological roles of these proteins are still under investigation and are not entirely elucidated at the present time
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