Abstract
Heat shock proteins (HSPs), which are members of the chaperone family of proteins, are essential factors for cellular responses to environmental stressors, such as hyperthermia, and are antiapoptotic. The transcription of HSPs is mainly controlled by heat shock transcription factor 1 (HSF1). In response to environmental stress, HSF1 forms a trimer, undergoes hyperphosphorylation, and is translocated to the nucleus. In this study, we show that upon heat shock treatment of cells, a WW domain-containing propyl-isomerase, PIN1, is able to colocalize to and associate with phospho-HSF1 at Ser(326) in the nucleus via its WW domain. This interaction is required for the DNA-binding activity of HSF1 and is consistent with the lower induction of HSPs in PIN1-deficient cells. This function of PIN1 is further demonstrated by in vivo refolding and survival assays, which have shown that PIN1-deficient cells are temperature sensitive and develop apoptosis upon exposure to an environmental challenge. Moreover, the reduced levels of HSPs in PIN1-deficient cells resulted in less efficient refolding of denatured proteins. Based on our results, we propose a novel role for PIN1 whereby it acts as a stress sensor regulating HSF1 activity in response to stress on multiple levels through the transcriptional activation of stress response elements in embryonic fibroblast cells, tumor cells, and neurons.