AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

Abstract

The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activity requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, and MEK1. mTOR, p38, and MEK1 all phosphorylated S326 but AKT1 was the more potent activator. Mass spectrometry showed that AKT1 phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. This study suggests that HSF1 activity is regulated by phosphorylation at specific residues that promote different stages of HSF1 activation. Furthermore, this is the first study to identify the functional role of these phosphorylation events.

HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

“…In breast cancer, HSF1 can be overexpressed with 10-15% of patients having HSF1 gene amplification (17). In addition, HSF1 can be hyperactivated stemming from increased proteotoxic stress and hyperactivation of activating kinases including AKT1, mTORC1, and p38 among others (21)(22)(23)(24)(25). A seminal finding describing the function of HSF1 in cancer identified that HSF1 has a unique transcriptional program in cancer cells, distinct from the heat stress response transcriptional program, that indicated HSF1 has several additional functions in cancer (26).…”