Hsp90 regulates hTERT subcellular localization and HSF1 directs its expression level

ZGAJNAR NR; LOTUFO C; GALIGNIANA MD

Leysin

Congreso; 9th International Conference on the Hsp90 Chaperone Machine; 2018

Cancer cells achieve proliferative immortality by upregulating telomerase. hTERT is the catalytic subunit with reverse-transcriptase activity, and form complexes with a functional RNA, Hsp90 and p23. Recently, we demonstrated that Hsp90-binding immunophilin FKBP51 is an antiapoptotic chaperone overexpressed in cancer cells that undergoes nuclear-mitochondrial trafficking. Both FKBP51 and FKBP52 associate to the hTERT?Hsp90 nuclear heterocomplex in a peptidylprolyl-isomerase (PPIase)-independent manner and enhance telomerase enzymatic activity in a PPIase-dependent fashion. The primarily nuclear localization of hTERT is favored by FKBP52 via the Hsp90?FKBP52?dynein retrotransport machinery, and by anchoring hTERT to nucleoskeleton structures. The disruption of the hTERT heterocomplex with radicicol or by overexpression of the TPR interacting peptide delocalizes nuclear hTERT to the cytoplasm. This Hsp90-free hTERT is degraded via proteasome unless it is targeted to mitochondria, where it seems to complement the antiapoptotic effects of FKBP51. Oxidative stimuli also disengage hTERT from nuclear structures favoring its nuclear export. The same type of stimulus (H2O2, arsenite, BSO, tert-butyl-hydroperoxide, etc.) increases hTERT expression. Because high ionic strength, high glucose, heat-shock, etc. also show similar effect, the HSF1 activation could be 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 HSF, even in the absence of stimuli. It is concluded that overall expression level of hTERT depends on HSF1 activation, whereas its subcellular localization is commanded by Hsp90.