THE HSP90-BINDING COCHAPERONE FK506-BINDING PROTEIN 51 IS A NOVEL MODULATOR OF TELOMERASE ENZYMATIC ACTIVITY

ZGAJNAR NR, DANERI BECERRA C, PATIÑO M, GALIGNIANA MD

Congreso; LXI Reunión Anual de SAIC; 2016

Immunophilins (IMMs) are a family of proteins that bind immunosuppressive drugs and show peptidylprolyl isomerase activity (PPIase). FKBP51 is an Hsp90-binding cochaperone able to bind the macrolide FK506, which in turn, abolishes PPIase activity. We have previously demonstrated that FKBP51 is a novel mitochondrial factor with antiapoptotic action that is highly expressed in cancer cell lines and tumour tissues. These systems show high telomerase activity, whose inverse transcriptase subunit, hTERT, is an Hsp90 client protein. Because both proteins, FKBP51 and hTERT, are highly expressed in tumours, and both of them form complexes with Hsp90, we postulated that FKBP51 could form complexes with hTERT regulating its enzymatic activity. Here we show that FKBP51 and its close-related partner FKBP52 (75% similitude) co-immunoprecipitates with hTERT-Hsp90 complexes. Such association is disrupted by the Hsp90-inhibitor radicicol, and due to the overexpression of the TPR-domain of the IMM, which is required to interact with the chaperone. Confocal images show a high colocalization score for hTERT and FKBP51, in particular when various stressing conditions such as oxidative stress, among others, favour the rapid nuclear accumulation of the IMM. When the stimulus persists, hTERT is exported to mitochondria, an event that could be related to the chaperoning action of FKBP51 after releasing hTERT from the telomeric regions where it is anchored. The cytoplasmic hTERT pool not imported to mitochondria (where it shows antiapoptotic actions) is targeted to proteosomal degradation. Importantly, measurements of telomerase activity demonstrated that FKBP51 greatly enhances the enzymatic activity, a key requirement to protect the shortening of chromosome ends and favor the rapid clonal expansion of the cells. In this regard, its close partner FKBP52 is functionally redundant. In short, this study demonstrates for the first time that IMMs are novel regulators of hTERT activity.