Genetic inactivation of essential HSF1 reveals an isolated transcriptional stress response selectively induced by protein misfolding

Abstract

Heat Shock Factor 1 (Hsf1) in yeast drives the basal transcription of key proteostasis factors and its activity is induced as part of the core heat shock response. Exploring Hsf1 specific functions has been challenging due to the essential nature of the HSF1 gene and the extensive overlap of target promoters with environmental stress response (ESR) transcription factors Msn2 and Msn4 (Msn2/4). In this study, we constructed a viable hsf1∆ strain by replacing the HSF1 open reading frame with genes that constitutively express Hsp40, Hsp70 and Hsp90 from Hsf1-independent promoters. Phenotypic analysis showed that the hsf1∆ strain grow slowly, is sensitive to heat as well as protein misfolding and accumulates protein aggregates. Transcriptome analysis revealed that the transcriptional response to protein misfolding induced by azetidine-2-carboxylic acid is fully dependent of Hsf1. In contrast, the hsf1∆ strain responded to heat shock through the ESR. Following HS, Hsf1 and Msn2/4 showed functional compensatory induction with stronger activation of the remaining stress pathway when the other branch was inactivated. Thus, we provide a long overdue genetic test of the function of Hsf1 in yeast using the novel hsf1∆ construct. Our data highlight that the accumulation of misfolded proteins is uniquely sensed by Hsf1-Hsp70 chaperone titration inducing a highly selective transcriptional stress response.

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway

“…HSF1 is a well-known transcription factor that maintains the cellular proteostasis network in response to the HSR in the cytosol and the UPR in the endoplasmic reticulum [ 22 ]. Thus, we investigated whether HSF1 is closely related to the induction of the expression of HSR- and UPR-related genes in USP7i-treated cells.…”

High Glucose Is a Stimulation Signal of the Salt–Tolerant Yeast Zygosaccharomyces rouxii on Thermoadaptive Growth

“…Matsumoto et al [ 28 ] found that the survival rate of Kluyveromyces marxianus decreased significantly without cell membrane damage, and trehalose was accumulated to eliminate heat–stressed ROS during heat shock at 50 °C for 20 min. It can be seen that the effects of high temperature stress on yeast cells are extensive and comprehensive, and the process of yeast cells adapting to high–temperature heat shock involves the regulation of multiple components such as the cell membrane, proteins and chromatin [ 29 , 30 , 31 ]. At present, we have some understanding of the mechanism of yeast (such as S. cerevisiae and Kluyveromyces marxianus ) adapting to high temperature stress, and most studies have mainly focused on short–term heat shock [ 32 , 33 ], but there are few studies on the mechanism of the high–temperature adaptation of Z. rouxii .…”