Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion

Maintenance of protein homeostasis, through inducible expression of molecular chaperones, is essential for cell survival under protein-damaging conditions. The expression and DNA-binding activity of heat shock factor 2 (HSF2), a member of the heat shock transcription factor family, increase upon exposure to prolonged proteotoxicity. Nevertheless, the specific roles of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained unknown. Here, we found that HSF2 is critical for cell survival during prolonged proteotoxicity. Strikingly, our RNA sequencing (RNA-seq) analyses revealed that impaired viability of HSF2-deficient cells is not caused by inadequate induction of molecular chaperones but is due to marked downregulation of cadherin superfamily genes. We demonstrate that HSF2-dependent maintenance of cadherin-mediated cell-cell adhesion is required for protection against stress induced by proteasome inhibition. This study identifies HSF2 as a key regulator of cadherin superfamily genes and defines cell-cell adhesion as a determinant of proteotoxic stress resistance

deThonel_Sourcedata_Fig2

HSF2 is acetylated by CBP and EP300 in normal conditions</p

deThonel_Sourcedata_Fig4

Modeling of CBP and HSF2 interaction.</p

deThonel_Sourcedata_FigureS6

Altered HSF2 protein levels and dysregulation of the stress response in RSTS.</p

deThonel_Sourcedata_FigureS11

RSTS iNPC and hCO characterization upon MG132 treatment.</p

deThonel_Sourcedata_FigureS1

deThonel_Figure-1</p

deThonel_Sourcedata_Fig6

Altered HSF2 protein levels and dysregulated stress response in cells from RSTS patients</p

deThonel_Sourcedata_Fig5

Impact of preventing or mimicking acetylation of lysine residues K128, K135, and K197 on HSF2 protein stability.</p

deThonel_Sourcedata_Fig7

HSF2-dependent dysregulated stress response and neurodevelopmental gene expression in cells from RSTS patients.</p

deThonel_Sourcedata_Fig1

HSF2 is expressed, acetylated, and interacts with EP300/CBP in neu- rodevelopmental contexts</p