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, PGC1a, 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 PGC1a physically interacts with HSF1 on HSP promoters and that cells and mice lacking PGC1a have decreased HSPs levels and are more sensitive to thermal challenges. Taken together, our findings suggest that PGC1a protects against hyperthermia by cooperating with HSF1 in the induction of a transcriptional program devoted to the cellular protection from thermal insults.

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