Synopsis

The heat shock response is triggered when cells are exposed to heat or another proteotoxic stress. The immediate effect of this stress exposure is denaturation of a significant fraction of cellular proteins, and the end result is increased levels of Hsp chaperones that accelerate refolding of stress-unfolded proteins and degradation by the ubiquitin-proteasome pathway. Stress-unfolded proteins also appear to be the primary signal for activating the key transcription factor, HSF1, which mediates stress-induced expression of hsp genes. HSF1 activation is repressed at the levels of homotrimerization and acquisition of transcriptional competence by Hsps and multichaperone complexes (Fig. 3). It is believed that most HSF1 molecules are dynamically associated with an Hsp90-p23-immunophilin complex in an unstressed cell. Stress-unfolded proteins accumulating in a stressed cell compete with HSF1 for Hsps and co-chaperones. As a result, HSF1 is released from the multichaperone complex and self-associates to form homotrimers. A fraction (whose importance is related to stress intensity) of trimeric HSF1 escapes capture by a repressive Hsp90- and FKBP52-containing multichaperone complex and other repressive interactions with Hsps, acquires transcriptional competence, and begins to transactivate hsp genes. Consequently, levels of Hsps rise. During recovery from a stress or during prolonged exposure to a mild to moderately severe stress, stress-unfolded proteins are either refolded or eliminated by proteolytic degradation. Levels of Hsps and co-chaperones available for interaction with HSF1 increase again. This is expected to result in formation of repressive interactions between HSF1 and Hsps and/or multichaperone complexes, accelerated chaperone-mediated disassembly of HSF1 trimers, and the eventual re-association of HSF1 polypeptide with Hsp90-p23-immunophilin complex. This direct control of HSF1 activity by Hsps and co-chaperones is modulated by several interactions/reactions that link HSF1 regulation to a wider set of stress-regulated aspects of cell metabolism and may serve to integrate multiple stress signals. These reactions include stress-induced activating and repressive phosphorylation of HSF1, which is, in part, mediated by ERK1, GSK3, JNK1, and CaMKII kinases. The activities of some of these kinases were increased in the stressed cell. Transcriptional activation of HSF1 is also enhanced by DAXX, a protein that only becomes available for interaction with HSF1 subsequent to stress-induced disintegration of PODs. Finally, HSF1-mediated hsp gene expression may be indirectly influenced by stress-induced and Hsp70-repressed sequestration of HSF1 in stress granules.

The author hopes that the present review has not only informed on what is known about the regulation of HSF1 and the heat shock response, but has also led the reader to recognize the large lacunae that still exist in our understanding. Clearly, one of the least understood aspects is the pathway of deactivation of HSF1. The mechanism (or mechanisms) by which HSF1

stress-induced release •phosphorylation PML •desumoylation PML^

HIPK1

activating phosphorylation of S230, S326

stress-induced release •phosphorylation PML •desumoylation PML^

HIPK1

POD:

h activating phosphorylation of S230, S326

repressive phosphorylation

Symplekin

CstF CPSF

stress .Activation?

Protein Kinases (CaMKII for S230) —

Daxx

(chromosomal location: 9q12) Stress Granules

(chromosomal location: 9q12) Stress Granules

satellite III transcripts repressive phosphorylation satellite III transcripts

Symplekin

CstF CPSF

Hsp pre-mRNA

Hsp mRNA

Qjsp90

Fig. 3 Schematicrepresentation ofvariousaspectsandmechanismsinvolvedinthe regulation of HSF1 activity and the heat shock response. 70, 52, and 40 refer to Hsp70, FKBP52, and Hsp40, respectively homotrimers are disassembled as well as the relationship between this mechanism and repressive phosphorylation and repressive chaperone interactions with trimeric HSF1 remain entirely unknown. Furthermore, the present understanding of the regulation of the heat shock response is largely based on results from cell culture studies. Continued examination of the response in complex organisms such as plants or metazoan animals, or their organs and tissues, will likely result in significant adjustments in our present thinking, in particular relating to interactions between HSF1 and other HSFs, and the role of different HSFs in specific differentiated cell types. Finally, it is noted that, to avoid duplication, a discussion of interactions between HSF1 (and the heat shock response) and other signaling pathways including apoptotic pathways and steroid receptor-mediated regulation was omitted.

Acknowledgements I thank Alexis Hall for the artwork and HSF Pharmaceuticals S.A. for supporting this project.

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