Regulation of Hsf1 by stress response crosstalk in Saccharomyces cerevisiae

Abstract

Heat shock factor 1 (Hsf1) is a conserved transcription factor involved in cellular response to folding stress. A simple model has been proposed in which Hsf1 monitors misfolded protein species through a negative feedback loop. Accumulation of misfolded proteins titrate inhibitory chaperones from Hsf1, which frees it to drive the expression of more chaperones. These chaperones in turn refold proteins and inhibit Hsf1. However, recent studies have demonstrated that Hsf1 monitors more than just misfolded proteins, and its exact role in cellular quality control has not been fully explored. Here, we demonstrated that two genetic perturbations affect the ability of Hsf1 to become active independent of the folding state of the cell.

We first identified the environmental stress response (ESR) in yeast as a suppressor of Hsf1 in aneuploidy, when cells have an inappropriate number of chromosomes. Through selective deactivation of a constitutive ESR, we allowed Hsf1 to become active. However, we also found that active Hsf1 could not compensate for the loss of the ESR, and aneuploid yeast lacking an ESR had decreased fitness. Furthermore, we showed that hyperactivation of the ESR suppressed Hsf1 activation during heat stress in euploid yeast, and protected them from lethal heat shock and aggregate formation. Follow up studies showed that both branches of the ESR, induced genes (iESR) and repressed genes (rESR), were responsible for the phenotypes associated with Hsf1 suppression and increased protein homeostasis.

I also investigated the uncharacterized gene AIM29, which greatly increases Hsf1 activity when deleted. After confirming previous findings, I found deletion of AIM29 did not cause folding stress, and it appears Hsf1 is activated by a mechanism independent of protein homeostasis. These studies demonstrate that Hsf1 activity can be affected by genetic changes that are not directly related to folding stress, the mechanisms of which still need to be identified.