| Abstract: | ["To cope with adverse environmental conditions like increased temperatures, oxidative stress, extreme pH, heavy metals or other noxious compounds or with physiological and pathophysiological imbalance of protein homeostasis all organisms evolved a homeostatic transcriptional response, the so-called heat shock response. The central regulator of the heat shock response is in all eukaryotic cells the heat shock transcription factor HSF1. In metazoans HSF1 is mostly monomeric in non-stressed cells. Upon heat shock HSF1 trimerizes and regulates transcription of more than 5000 genes, consequently increasing the levels of molecular chaperones, proteases, and many other stress-related proteins and decreasing a host of housekeeping proteins.\r\nUsing purified proteins, we show that HSF1 is a temperature sensor integrating over temperature and time spend at elevated temperatures. We further elucidated the molecular mechanism how Hsc70 represses the transcriptional activation of HSF1. Our data demonstrate that the molecular chaperone Hsc70 together with its cochaperone Hdj1 dissociate HSF1 trimers into monomers by binding to a specific site near the trimerization domain. We show that Hsc70 utilizes an entropic pulling mechanism but that entropic pulling alone does not explain the action of Hsc70. Finally, our data explain why HSF1 monomerization and transcriptional inactivation is exquisitely responsive to Hsc70 concentration. We propose an integrative model of the heat shock response."] |
