Increasing Saccharomyces cerevisiae stress resistance, through the overactivation of the heat shock response resulting from defects in the Hsp90 chaperone, does not extend replicative life span but can be associated with slower chronological ageing of nondividing cells

Abstract

Recent studies on Drosophila and Caenorhabditis elegans indicate that increases in stress resistance result in a longer chronological life span, an effect that must operate primarily on the postmitotic tissues of the adult. Stress resistance can be increased through decreases in Hsp90 chaperone activity, since Hsp90 acts to downregulate the activity of heat shock transcription factor. This study investigated whether the increases in stress resistance associated with reduced Hsp90 chaperone activity influence ageing in the budding yeast Saccharomyces cerevisiae, ageing being measured either as the replicative (nonchronological) senescence of budding cells or as the chronological ageing of non-dividing (stationary phase) cultures. Overactivation of the heat shock response caused no slowing of replicative senescence. In some situations though it was associated with a longer chronological life span of stationary cells, the yeast equivalent of the postmitotic state. This is consistent with the idea that stress resistance exerts its life span-extending effects primarily in postmitotic cells and tissues.

Casein kinase 2 phosphorylation of Hsp90 threonine 22 modulates chaperone function and drug sensitivity

“…We confirmed that yHsp90-T22I displayed a higher basal and heat-induced (39°C for 40 min) Hsf1 activity compared to WT cells [39] (Figure 3B), while Hsf1 activity was significantly diminished in the phospho-mimetic yHsp90-T22E mutant. At the same time, Hsf1 activity in yHsp90-T22A mutant yeast was equivalent to that of yeast expressing WT yHsp90.…”

Regulation of the Hsf1-dependent transcriptome via conserved bipartite contacts with Hsp70 promotes survival in yeast

“…Studies in metazoan systems demonstrated association between Hsps, most notably Hsp90, and HSF1 both in vivo and in vitro (8 -10). A regulatory chaperone-Hsf1 interaction in yeast was long supported by genetic studies in which the loss of constitutive Hsp70 or loss of a functional Hsp90 led to derepression of Hsf1 activity (11)(12)(13). Additionally, the constitutively expressed Hsp70 Ssa1 was found to utilize two surfaceexposed cysteine residues to regulate Hsf1 as a sensor for thiolreactive stress (14).…”

Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges

“…Hsp90 is a negative regulator of heat shock transcription factor 1 (HSF1), such that its inhibition leads to the formation of the active HSF-1 homotrimers needed for the induction of the heat shock response [44,45]. At least in the yeast model system, a point mutation in Hsp90 is capable of rendering HSF-1 constitutively active [46]. …”