Heat shock factor 1 (Hsf1) is transcriptionally activated following exposure of mammalian cells to environmental insults and pathological conditions. The function of Hsf1 as a protector of cells and organisms towards a range of stress stimuli has been well-documented. However, how different Hsf1 post-transcriptional modifications affect its function in vivo is not understood. Hsf1 transcriptional activity is in part regulated by phosphorylation. Hsf1 phosphorylation of amino acid residues at S303 and S307 has been shown to repress Hsf1 transcriptional activity under normal physiological growth conditions. In this study, we used a knock-in mouse model where serine residues S303 and S307 were mutated to alanine (S303A/S307A) in order to reveal the relevance of these phosphorylation sites on Hsf1 activity in vitro and in vivo. Our results indicate that Hsf1303A/307A protein becomes more stable, but remains mostly cytoplasmic under normal physiological growth conditions. However, in contrast to wild type, the Hsf1303A/307A protein exhibits reduced threshold of activation following exposure of cells to a very mild heat stress, or when mice are placed under the conditions of nutrient stimulation. The in vivo consequence of the Hsf1303A/307A mutant protein expression results in an age-dependent obesity, fatty liver disease and insulin resistance. Taken together, these data point to the importance of maintaining dynamic regulation of Hsf1 responses including resolution of Hsf1 activation to restore repression of Hsf1 through phosphorylation of S303 and/or S307. Specifically, we show that the inability to phosphorylate Hsf1 at these amino acid residues can play a role in the development of age-dependent metabolic diseases, such as obesity and insulin resistance.
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