Novel aspects of heat shock factors

Numerous proteins are synthesized, correctly folded, degraded and form networks with other proteins in cells to carry out their functions. To maintain cellular integrity against stress that causes protein misfolding, cells control the quality and quantity of the proteins being synthesized. This mechanism is called protein homeostasis or proteostasis. One of the major adaptive responses is the heat shock response, which was first described in 1962 by Ritossa who observed chromosome puffing in Drosophila after exposure to high temperature. In 1974, Tissieres and Mitchell showed that the appearance of this puffing was associated with the synthesis of a small number of new proteins, termed heat shock proteins (HSPs). After the finding in 1978 by Schlesinger that high temperature induced the synthesis of similar proteins in cultured avian cells, comparable responses have been reported in all organisms examined. The heat shock response is characterized by the induction of a set of major HSPs such as HSP90 and HSP70, which act as molecular chaperones that facilitate the folding and assembly of proteins and inhibit their misfolding. The expression of HSP genes in eukaryotes is regulated mainly at the level of transcription by heat shock factors (HSFs). An imbalance of protein homeostasis is associated with misfolding-related pathological conditions such as neurodegenerative disorders, and HSFs have a strong impact on the suppression of protein-misfolding disorders by inducing the expression of genes encoding major HSPs. During the past few years, comprehensive analysis has revealed numerous HSF targets including HSP and non-HSP genes, the expression of which is regulated differentially by HSF family members. The minireview by Fujimoto and Nakai discusses recent advances in evolution of the vertebrate HSF genes and on adaptation by HSF-mediated changes of gene expression. HSF1 activation in mammals is controlled mainly by two steps: the acquisition of DNA-binding activity, which is accompanied by a monomer-to-trimer transition, and transcriptional activity. Major HSPs negatively regulate both steps by interacting directly with HSF1. Furthermore, HSF1 is covalently modified by phosphorylation and sumoylation, which regulate the acquisition of DNA-binding activity or transcriptional activity. It was recently found that the post-transcriptional regulation of HSF expression and the direct interaction between distinct HSFs are integral parts of the regulatory mechanism, in addition to newly identified HSF acetylation. Björk and Sistonen review these advances in the regulation of the HSF family. Importantly, the trimerization of HSFs is required for stable binding to the heat shock element (HSE) that is composed of inverted repeats of a consensus nGAAn pentanucleotide. The precise interaction of the HSE with the HSF family and HSF-mediated changes of chromatin structure have been extensively studied in recent years, and these are reviewed by Sakurai and Enoki. In addition to their role in HSP expression, HSFs play critical roles in developmental processes such as gametogenesis, neurogenesis and maintenance of sensory organs. Although precise mechanisms are currently unclear, accumulating evidence suggests that HSFs could regulate the expression of development-related genes as well as HSP genes. Abane and Mezger review developmental aspects of the HSF family and discuss recent understanding of the molecular mechanisms. Historically, induction of HSP gene expression by HSF is recognized as a unique hallmark of the heat shock response. In this minireview series we assess a new paradigm of the heat shock response: changes of target gene expression by the HSF family members under both stress and nonstress conditions. We hope it could offer a way into further research on the heat shock response with a wide-ranging biological significance.