Human cells respond to heat stress by inducing the binding of a preexisting transcriptional activator (heat shock factor, HSF) to DNA. Human heat shock factor 1 (HSF1) stimulates transcription from heat shock protein genes following stress. HSF1 is constitutively expressed in most tissues and cell types and appears to be regulated primarily through posttranslational mechanisms.
In the absence of stress, the DNA-binding activity and trans-activating capacity of HSF1 are subject to negative regulation, and the majority of HSF1 exists in an inert monomeric form, diffusely distributed in the nucleus. Upon the transition to protein-damaging stress conditions, HSF1 is rapidly converted into a transcriptionally active form, proceeding through a multistep pathway involving a monomer-to-trimer transition and a subsequent gain of DNAbinding activity, nuclear accumulation, and extensive posttranslational modifications. The proteotoxic signals that initiate HSF1 activation can be of various origins; in addition to elevated temperatures or hyperthermia, HSF1 is activated by oxidative stress, heavy metals, and bacterial and viral infections, as well as by small-molecule modulators.
Given the central role of HSF1 in directing the transcription of hsp genes and the need for proteome maintenance for increased life span, it is perhaps not surprising that HSF1 is required also for long life. In C. elegans, downregulation of HSF-1 by RNAi reduces life span 30–40% and accelerates the formation of protein aggregates associated with Huntington’s and Alzheimer’s diseases. Similarly, nematodes expressing additional copies of the hsf-1 gene are resistant to hyperthermia and oxidative stress, and they live approximately 40% longer than their wild-type counterparts.