Abstract
Heat shock proteins (HSPs) are required for the clearance of damaged and aggregated proteins and have important roles in protein homeostasis. It has been shown that the heat shock transcription factor, HSF1, orchestrates the transcriptional induction of these stress-regulated chaperones; however, the coregulatory factors responsible for the enhancement of HSF1 function on these target genes have not been fully elucidated. Here, we demonstrate that the cold-inducible coactivator, PGC1α, also known for its role as a regulator of mitochondrial and peroxisomal biogenesis, thermogenesis and cytoprotection from oxidative stress, regulates the expression of HSPs in vitro and in vivo and modulates heat tolerance. Mechanistically, we show that PGC1α physically interacts with HSF1 on HSP promoters and that cells and mice lacking PGC1α have decreased HSPs levels and are more sensitive to thermal challenges. Taken together, our findings suggest that PGC1α protects against hyperthermia by cooperating with HSF1 in the induction of a transcriptional program devoted to the cellular protection from thermal insults.
Highlights
Hyperthermia, the classic inducer of Heat shock proteins (HSPs), leads to heat stroke and can arise in genetically predisposed subjects with mutations in the ryanodine receptor gene[8] and in subjects with adverse reactions to drugs such as selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants and volatile anesthetic gases.[9]
Upon physiological stresses resulting from hyperthemia or oxidative insults, heat shock factor 1 (HSF1) is released from the chaperone complex and, upon trimerization, it translocates into the nucleus and binds to heat shock-responsive elements (HSEs) present on target gene promoters to initiate their transcriptional activation.[12]
Loss-of-function studies showed that PGC1α is required for HSF1 activation of HSPs and protection from hyperthermia
Summary
Hyperthermia, the classic inducer of HSPs, leads to heat stroke and can arise in genetically predisposed subjects with mutations in the ryanodine receptor gene[8] and in subjects with adverse reactions to drugs such as selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants and volatile anesthetic gases.[9]. Upon physiological stresses resulting from hyperthemia or oxidative insults, HSF1 is released from the chaperone complex and, upon trimerization, it translocates into the nucleus and binds to heat shock-responsive elements (HSEs) present on target gene promoters to initiate their transcriptional activation.[12] It has been shown that HSF1-null fibroblasts are more susceptible to heat-induced apoptosis because of the absence of HSP induction[13] and that HSF1-null mice fail to raise HSP levels in response to thermal insults,[14] suggesting critical roles of HSF1 in the regulation of HSPs in stress defense. Our results establish PGC1α as a new critical orchestrator of thermotolerance in cooperation with HSF1
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