Research in my laboratory is directed at understanding the molecular importance of the heat shock response (HSR) in cellular metabolism, aging and disease. The HSR is a universally conserved pathway that allows cells to recover from protein damage induced by various stressors. The heat shock transcription factor HSF1, the master regulator of the HSR, transcriptionally activates molecular chaperones and other genes that are essential for cell survival. We are interested in understanding how the HSR can be modulated to provide therapeutic benefit for a variety of disease states. Upregulation of the HSR could be therapeutically beneficial in various neurodegenerative diseases. Conversely, downregulation of the HSR could be beneficial in cancer treatment.
We have recently found that HSF1 is regulated by the longevity factor SIRT1. SIRT1 is a metabolically regulated deacetylase that is required for full HSF1 transcription. We have shown that HSF1 is acetylated within its DNA binding domain at lysine 80, and that acetylation at this site disrupts DNA binding. Deacetylation of this residue by SIRT1 maintains HSF1 in a DNA-binding competent state, activating HSF1-dependent transcription and the HSR. We are interested in further investigating the links between the heat shock response and cell metabolism and lifespan.