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Heat shock factors: integrators of cell stress, development and lifespan

Nature Reviews Molecular Cell Biology volume 11, pages 545–555 (2010)Cite this article

Subjects

Key Points

  • Heat shock factors (HSFs) are essential for all organisms to survive exposures to stress, as they bind heat shock elements to induce transcription of heat shock proteins (HSPs). In addition, the HSFs are important regulators involved in development, lifespan and disease, thereby integrating pathways of stress responses and normal physiology.

  • The mammalian HSF family consists of four members: HSF1, HSF2, HSF3 and HSF4. Distinct HSFs possess unique and overlapping functions, with a great variation in expression patterns, post-translational modifications (PTMs) and interacting protein partners.

  • HSFs are composed of functional domains, of which the DNA-binding domain is best preserved. The HSF1 activation–attenuation cycle involves trimerization, strict regulation by multiple PTMs, such as acetylation, phosphorylation and sumoylation, and feedback from HSPs.

  • Functional crosstalk between HSF family members facilitates the fine-tuning of HSF-mediated gene regulation. HSF-knockout mouse models have made it possible to identify many targets, which have further extended the impact of HSFs in developmental processes, such as oogenesis, corticogenesis and spermatogenesis.

  • The ability to sense and respond to environmental challenges is important for lifespan, and HSF1 is a longevity factor that prevents global instability of the proteome during ageing. The life-promoting function of HSF1 is strictly controlled by the insulin and insulin-like signalling pathway in Caenorhabditis elegans.

  • HSF1 is a potent modifier of tumorigenesis and HSF1 deficiency in mice counteracts tumour initiation and progression. HSF1 is therefore a potential cancer drug target. As many human, age-related pathologies are associated with stress and misfolded proteins, several small-molecule activators and inhibitors of HSFs could be used for pharmacologic modulation of HSF-mediated gene regulation.

Abstract

Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.

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Figure 1: The mammalian HSF machinery.
Figure 2: Members of the mammalian HSF family.
Figure 3: HSF1 undergoes multiple PTMs on activation.
Figure 4: Interactions between different HSFs provide distinct functional modes in transcriptional regulation.

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Acknowledgements

We apologize to our colleagues whose original work could only be cited indirectly owing to space limitations. Members of our laboratories are acknowledged for valuable comments on the manuscript. Our own work is supported by The Academy of Finland, The Sigrid Jusélius Foundation, The Finnish Cancer Organizations and Åbo Akademi University. The image in box 2 is courtesy of A. Sandqvist, Department of Biosciences, Åbo Akademi University, Turku, Finland.

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Authors and Affiliations

  1. Department of Biosciences, Åbo Akademi University, BioCity, 20520, Turku, Finland

    Malin Åkerfelt & Lea Sistonen

  2. Centre for Biotechnology, University of Turku and Åbo Akademi University, BioCity, 20520, Turku, Finland

    Malin Åkerfelt & Lea Sistonen

  3. Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, 60208, Illinois, USA

    Richard I. Morimoto

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  1. Malin Åkerfelt
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Correspondence to Lea Sistonen.

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Richard I. Morimoto is a co-founder, shareholder and paid consultant for Proteostasis Therapeutics Inc., which is developing drugs that could be pharmacologic chaperones and proteostasis regulators.

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Glossary

Polytene chromosome

A chromosome that undergoes multiple rounds of DNA replication, without cell division, and produces many sister chromatids that remain synapsed together; for example, in larval salivary glands of D. melanogaster.

Proteostasis

Also called protein homeostasis, this refers to the control of the concentration, three-dimensional structure, binding interactions and cellular location of individual proteins making up the proteome.

S1 mapping

A method for mapping precursor or mature mRNAs that correspond to particular DNA sequences using the S1 nuclease enzyme.

Coiled coil

A structural motif in proteins, in which α-helices are coiled together like the strands of a rope, most commonly as dimers and trimers.

Leu zipper

A common three-dimensional structural motif in regulatory proteins that functions as an oligomerization domain and generates adhesion forces in parallel α-helices.

ψKxExxSP

Many SUMO substrates contain this extended consensus sequence (called the PDSM), in which ψ denotes a branched hydrophobic amino acid, the Lys is the SUMO acceptor and x is any amino acid.

Sirtuin

A class of proteins that posses either histone deacetylase or monoribosyltransferase activity. SIRT1 is activated by resveratrol, which is a phytoalexin produced naturally by several plants when under attack by pathogens, and has been suggested to trigger mechanisms that counteract ageing-related effects in animals.

Paused RNA polymerase II

An RNA polymerase II molecule that is engaged in transcription but has arrested after synthesizing ∼25 nucleotides; for example, on the HSP70 promoter under non-heat-shock conditions.

Mediator complex

A multiprotein complex that functions as a transcriptional co-activator and binds to the C-terminal domain of the RNA polymerase II holoenzyme, acting as a bridge between this enzyme and transcription factors.

Preinitiation complex

A large protein complex that is necessary for the transcription of protein-coding genes in eukaryotes and typically consists of six general transcription factors: TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH.

Satellite III repeat

A highly repetitive DNA element that is so called because repetitions of a short DNA sequence tend to produce a different frequency of the nucleotides adenine, cytosine, guanine and thymine compared with bulk DNA.

Germinal vesicle breakdown

The process whereby a greatly enlarged nucleus of an egg in prophase of the first meiotic division breaks down, permitting entry into metaphase I.

Cortical plate

The middle layer of the cerebral cortex. The cerebral cortex is formed during development, and neurons migrate from the ventricular zone to form layers. The cortical plate will form the deep layers of the mature cortex.

Ventricle

A brain structure that contains cerebrospinal fluid. There are four cerebral ventricles: the paired lateral ventricles that are large and C shaped, and the third and fourth ventricles in the midline.

Cortical lamination

The characteristic distribution of neuronal cell types and their connections in the six main layers of the cerebral cortex.

Neuronal migration

The process whereby neurons migrate from their place of origin or birth to their final position in the brain by, for example, radial migration or tangential migration.

Pachytene spermatocyte

A male gametocyte that derives from a spermatogonium, resides in the seminiferous tubules of the testis and is in the developmental stage of spermatogenesis, before which meiosis occurs.

Round spermatid

A haploid male gamete derived from spermatocyte division. As a result of meiosis, each round spermatid contains only half of the genetic material present in the original spermatocyte.

Sex chromosomal multi-copy gene

A large amplified region that comprises palindromic or tandem segmental duplications, contains multi-copy gene families and resides in the X and Y chromosomes.

Sex chromatin

The complex combination of DNA and proteins that makes up chromatin of the X and Y chromosomes during spermatogenesis.

Cataract

Clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light.

Unfolded protein response

A cellular stress response that is activated by an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum.

Non-oncogene addiction

The increased dependence of cancer cells on the normal cellular functions of certain genes, which are not classical cancer genes or oncogenes but, if targeted, they could be equally effective at treating cancer.

Aneuploidy

An abnormal number of chromosomes generated during cell division when the chromosomes do not separate properly between the two daughter cells. This is a characteristic of cancer cells.

PolyQ

A protein sequence that consists of multiple (typically tens to hundreds) Glu repeats. Several inheritable neurodegenerative disorders are polyQ diseases, characterized by a mutation that extends a CAG (which encodes Glu) repeat in a specific gene (for example, huntingtin (HTT) in Huntington's disease) beyond a certain length.

Rheostat

An adjustment device (a term borrowed from electronics).

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Åkerfelt, M., Morimoto, R. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11, 545–555 (2010). https://doi.org/10.1038/nrm2938

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