Role of HSF1 phopshorylation in heat shock response

Abstract

Highly conserved, molecular chaperones, known as Heat Shock Proteins (HSPs), assist in protein folding and perform quality‐control process. Impaired activity of HSPs results in uncontrolled protein aggregation. Inducible transcription of HSPs is driven by Heat Shock Response, mechanism strictly regulated by Heat Shock Factor 1 (HSF1). Upon proteotoxic insult, HSF1 undergoes complex post‐translational modifications and multistep activation process, involving trimerization, gain of DNA‐binding activity and transactivation capacity. Past studies have taken for granted that the phosphorylation of HSF1 is required for its transcriptional activity, but experimental evidence is still missing. Phosphorylation of HSF1 mainly occurs within the regulatory domain (RD), a region of HSF1 shown to be a master regulator of HSF1 transactivation capacity. The goal of this project is to elucidate the role of HSF1 phosphorylation. Using phosphorylation‐deficient HSF1 mutant, where all known phosphorylation sites residing within the RD are mutated to alanines. Generated mutant, not only is stress inducible transcription factor, but also more potent than wild‐type version of HSF1 in terms of gene expression. This results indicate that phosphorylation within regulatory domain is not required for stress inducible activation of HSF1 but also is an inhibitory mechanism upon stress stimuli.