HSF1-dependent regulatory mechanism of Hsp90-binding immunophilins on hTERT subcellular localization and biological action

GALIGNIANA MD

Paris

Congreso; European Oncology Conference 2020; 2020

European Society of Oncology

Cancer cells achieve proliferative immortality by up-regulating telomerase. hTERT is the telomerase catalytic subunit responsible for the reverse-transcriptase activity. hTERT forms oligomeric complexes with a template functional RNA, the chaperone Hsp90, the co-chaperone p23, and other accessory proteins. Recently, our laboratory demonstrated that a significant pool of the Hsp90-binding immunophilin FKBP51 is located in mitochondria. FKBP51 shows antiapoptotic action, is overexpressed in cancer cells, and undergoes nuclear-mitochondrial trafficking upon the onset of stress. In this study it is demonstrated that FKBP51 nuclear accumulation depends on the activation of the transcription factor HSF1. In the nucleus, FKBP51 and also its highly homologous partner FKBP52 bind to the hTERT?Hsp90 nuclear heterocomplex in a peptidylprolyl-isomerase (PPIase)-independent manner. Both immunophilins enhance telomerase enzymatic activity in a PPIase-dependent fashion. The basal nuclear localization of hTERT is favored by FKBP52 due to two reasons: a) its involvement in the Hsp90?FKBP52?dynein-dependent mechanism for hTERT cytoplasmic transport towards the nucleus, and b) by anchoring hTERT to the nucleoskeleton matrix. The disruption of the hTERT heterocomplex with the Hsp90 inhibitor radicicol or due to the overexpression of the Hsp90-binding TPR peptide, delocalizes hTERT from nucleus to cytoplasm, demonstrating a cardinal role of the chaperone in this process. On the other hand, the Hsp90-free hTERT becomes unstable and is targeted to proteasome degradation, unless hTERT is translocated to mitochondria, where it seems to complement the overall antiapoptotic action of FKBP51. Oxidative stimuli (H2O2, arsenite, BSO, tert-butyl-hydroperoxide, etc.) also disengage hTERT from nuclear structures favoring its nuclear export. Importantly, oxidative stress increases hTERT expression. Because several stimuli such as high ionic strength, high glucose, heat-shock, etc. also show similar effect, it was hypothesized that the HSF1 activation is involved. This was confirmed due to the lack of hTERT induction in HSF1-KO cells compared to wild-type cells, and by the high basal expression of hTERT due to the mere overexpression of HSF1, even in the absence of stimuli. It is concluded that: a) the nuclear translocation of FKBP51 from mitochondria depends on the activation of HSF, b) the expression level of hTERT also depends on HSF1 activation, and c) the subcellular localization and stability of hTERT is commanded by Hsp90.