Trends in Cell Biology
Volume 27, Issue 12, December 2017, Pages 895-905
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Review
Rethinking HSF1 in Stress, Development, and Organismal Health

https://doi.org/10.1016/j.tcb.2017.08.002Get rights and content

Trends

The activity of HSF1 in response to heat shock and other forms of cell stress conditions is tuned to the proliferative and metabolic status of the cell.

The HSR can be regulated in a cell non-autonomous manner through intertissue signaling to communicate stress signals and to ensure a coordinated organismal wide proteostatic response.

During development and in carcinogenesis, HSF1 directs transcriptional programs that are distinct from the HSR.

The transcriptional regulatory mechanism employed by HSF1 in development is uncoupled from the HSR through partnership with other transcription factors.

The heat shock response (HSR) was originally discovered as a transcriptional response to elevated temperature shock and led to the identification of heat shock proteins and heat shock factor 1 (HSF1). Since then HSF1 has been shown to be important for combating other forms of environmental perturbations as well as genetic variations that cause proteotoxic stress. The HSR has long been thought to be an absolute response to conditions of cell stress and the primary mechanism by which HSF1 promotes organismal health by preventing protein aggregation and subsequent proteome imbalance. Accumulating evidence now shows that HSF1, the central player in the HSR, is regulated according to specific cellular requirements through cell-autonomous and non-autonomous signals, and directs transcriptional programs distinct from the HSR during development and in carcinogenesis. We discuss here these ‘non-canonical’ roles of HSF1, its regulation in diverse conditions of development, reproduction, metabolism, and aging, and posit that HSF1 serves to integrate diverse biological and pathological responses.

Section snippets

HSF1 Directs the Dynamic HSR for Stress Adaptation and Proteostasis

The function of HSF1 that has been studied most extensively is its role in the HSR (Box 1), an evolutionarily conserved cellular defense mechanism which protects cells against proteotoxicity associated with misfolding, aggregation, and proteome mismanagement [1]. Protein quality-control machinery comprises the proteostasis network (PN) and is essential for all aspects of protein biogenesis, cellular robustness, organismal lifespan, and stress resilience [1]. HSF1 and its transcriptional targets

Regulation of HSF1 by the Proliferative and Metabolic State of the Cell

Among the known regulators of HSF1 are proteins that also function in growth factor signaling or nutrient-sensing pathways (Figure 2), suggesting that HSF1 and the HSR are influenced by the proliferative and metabolic state of the cell, thus providing a means for the cell to tailor the activity of HSF1 and the potency of the HSR to specific needs and cellular contexts. For example, MEK kinase of the RAS/MAPK pathway phosphorylates HSF1 at Ser326, and this promotes both HSF1 nuclear

HSR Is Subject to Cell Non-Autonomous Regulation in Metazoans

Because the HSR is influenced by the proliferative and metabolic state of the cell, how do animals coordinate HSF1 activity among different cell types and tissues to achieve organismal protection against cell stress conditions? Studies in Caenorhabditis elegans (C. elegans) provided the initial evidence for spatial and temporal control of HSF1 at the organismal level by cell non-autonomous regulation by neuronal signaling. For example, animals deficient in thermosensory neuron function are

HSF1 Directs Transcriptional Programs That Are Uncoupled From the HSR

Because HSF1 and the HSR are closely intertwined, it is not unexpected that new roles for HSF1 in growth, development, reproduction, and longevity have been attributed to the HSR. However, there is now increasing evidence from several biological systems that HSF1 is important for diverse ‘non-stress’ conditions including development 26, 40, energy metabolism [27], programmed cell death 41, 42, and carcinogenesis 28, 43. For these non heat-shock conditions, the transcriptomes regulated by HSF1

Activation and Regulation of HSF1 in the Absence of Cell Stress Conditions

How is HSF1 activated in the absence of proteotoxic stress conditions of the HSR? In cancer cells, the genomic occupancy of HSF1 decreases when translation is inhibited [50]. Similarly to the proposed role for misfolded proteins in derepression of HSF1, the increased flux of nascent polypeptides and newly synthesized proteins in cancer cells could also titrate chaperones away from HSF1 for nascent folding and maturation, thereby releasing HSF1 to activate transcription. Many of the regulators

Concluding Remarks

Cellular and organismal health requires optimal proteostasis, in which HSF1 plays an essential role in responding to and protecting against proteotoxic damage. Protein misfolding and aggregation underlie the pathologies of many age-related human diseases, most notably neurodegenerative and metabolic disorders [1]. For these diseases the ability to restore and enhance different arms of the PN to prevent imbalance and suppress aggregation and proteotoxicity may show promise. However, a greater

Acknowledgments

The authors thank the members of the laboratory of R.I.M. for their support and helpful discussion of the manuscript. J.L. was supported by postdoctoral awards from the National Ataxia Foundation, the BrightFocus Foundation for Alzheimer’s Disease Research, the Chicago Biomedical Consortium, and the Northwestern University Lung Sciences Training Program. J.P.L. was supported by a Postdoctoral Fellowship from the Amyotrophic Lateral Sclerosis (ALS) Association and a David Phillips Fellowship

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