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Regulation of heat shock transcription factors and their roles in physiology and disease

Key Points

  • Heat shock transcription factors (HSFs) have broad roles in stress resistance that encompass protection from protein misfolding, inflammation and environmental insults.

  • Structural biology studies reveal a new model for how HSFs bind to their target DNA sequence, whereby the DNA-binding domain of HSFs is exposed to the solvent. In this model, the different HSF isoforms would expose biochemically distinct surfaces, which can be subjected to differential regulation by protein–protein interactions and post-translational modifications to modulate abundance and activity of HSFs.

  • Accordingly, HSFs activate and repress genes that modulate metabolism, survival and proliferation in a context-dependent manner.

  • HSF1 stability and function are compromised in neurodegenerative diseases caused by protein misfolding, and this dysfunction contributes to disease progression.

  • Signalling pathways in cancer cells and tumour stroma activate HSF1 through mechanisms distinct from protein misfolding stress.

Abstract

The heat shock transcription factors (HSFs) were discovered over 30 years ago as direct transcriptional activators of genes regulated by thermal stress, encoding heat shock proteins. The accepted paradigm posited that HSFs exclusively activate the expression of protein chaperones in response to conditions that cause protein misfolding by recognizing a simple promoter binding site referred to as a heat shock element. However, we now realize that the mammalian family of HSFs comprises proteins that independently or in concert drive combinatorial gene regulation events that activate or repress transcription in different contexts. Advances in our understanding of HSF structure, post-translational modifications and the breadth of HSF-regulated target genes have revealed exciting new mechanisms that modulate HSFs and shed new light on their roles in physiology and pathology. For example, the ability of HSF1 to protect cells from proteotoxicity and cell death is impaired in neurodegenerative diseases but can be exploited by cancer cells to support their growth, survival and metastasis. These new insights into HSF structure, function and regulation should facilitate the development tof new disease therapeutics to manipulate this transcription factor family.

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Figure 1: Heat shock transcription factor 1 activation cycle.
Figure 2: Structural insights into heat shock transcription factor–DNA interaction topology.
Figure 3: Heat shock transcription factor 1 at the forefront of metabolic regulation.
Figure 4: Heat shock transcription factor 1 inactivation or depletion is a common defect in neurodegenerative disease.
Figure 5: Distinct regulation of heat shock transcription factor 1 in cancer and neurodegenerative disease.

References

  1. Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545–555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Anckar, J. & Sistonen, L. Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu. Rev. Biochem. 80, 1089–1115 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Gomez-Pastor, R. et al. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nat. Commun. 8, 14405 (2017). This publication reported a mechanism for the dampened expression of chaperones in polyQ expansion disease through the targeted degradation of HSF1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mendillo, M. L. et al. HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150, 549–562 (2012). This work identifies the HSF1 cancer gene signature, a set of genes that are largely distinct from those activated by heat shock stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scherz-Shouval, R. et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158, 564–578 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vihervaara, A. et al. Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells. Proc. Natl Acad. Sci. USA 110, E3388–E3397 (2013). This work describes the comprehensive genomic binding profiles of HSF1 and HSF2 during stress and in mitotically arrested cells.

    Article  CAS  PubMed  Google Scholar 

  7. Kim, E. et al. NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Hum. Mol. Genet. 25, 211–222 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mercier, P. A., Winegarden, N. A. & Westwood, J. T. Human heat shock factor 1 is predominantly a nuclear protein before and after heat stress. J. Cell Sci. 112, 2765–2774 (1999).

    CAS  PubMed  Google Scholar 

  9. Hentze, N., Le Breton, L., Wiesner, J., Kempf, G. & Mayer, M. P. Molecular mechanism of thermosensory function of human heat shock transcription factor Hsf1. eLife 5, e11576 (2016). This work identifies mechanisms for intrinsic thermosensing by HSF1.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Neef, D. W., Jaeger, A. M. & Thiele, D. J. Genetic selection for constitutively trimerized human HSF1 mutants identifies a role for coiled-coil motifs in DNA binding. G3 (Bethesda) 3, 1315–1324 (2013).

    Article  CAS  Google Scholar 

  11. Jaeger, A. M., Pemble, C. W., Sistonen, L. & Thiele, D. J. Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors. Nat. Struct. Mol. Biol. 23, 147–154 (2016). Structural biology studies demonstrated a new model for HSF2 binding to DNA and elucidated key regulatory distinctions between HSF1 and HSF2 via the DBD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rabindran, S. K., Haroun, R. I., Clos, J., Wisniewski, J. & Wu, C. Regulation of heat shock factor trimer formation: role of a conserved leucine zipper. Science 259, 230–234 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Ahn, S. G. & Thiele, D. J. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev. 17, 516–528 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gothard, L. Q., Ruffner, M. E., Woodward, J. G., Park-Sarge, O. K. & Sarge, K. D. Lowered temperature set point for activation of the cellular stress response in T-lymphocytes. J. Biol. Chem. 278, 9322–9326 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Jurivich, D. A., Pachetti, C., Qiu, L. & Welk, J. F. Salicylate triggers heat shock factor differently than heat. J. Biol. Chem. 270, 24489–24495 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Nakai, A. (ed.) Heat Shock Factor. (Springer, 2016).

    Book  Google Scholar 

  17. Shi, Y., Mosser, D. D. & Morimoto, R. I. Molecular chaperones as HSF1-specific transcriptional repressors. Genes Dev. 12, 654–666 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Neef, D. W. et al. A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1. Cell Rep. 9, 955–966 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sivéry, A., Courtade, E. & Thommen, Q. A minimal titration model of the mammalian dynamical heat shock response. Phys. Biol. 13, 066008 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Zou, J., Guo, Y., Guettouche, T., Smith, D. F. & Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell 94, 471–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Pernet, L. et al. HDAC6–ubiquitin interaction controls the duration of HSF1 activation after heat-shock. Mol. Biol. Cell 25, 4187–4194 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007). This early work described a key function for HSF1 in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jiang, Y. Q. et al. Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer's disease. Brain Res. 1519, 105–111 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Goetzl, E. J. et al. Low neural exosomal levels of cellular survival factors in Alzheimer's disease. Ann. Clin. Transl Neurol. 2, 769–773 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee, Y. J. et al. HSF1 as a mitotic regulator: phosphorylation of HSF1 by Plk1 is essential for mitotic progression. Cancer Res. 68, 7550–7560 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Elsing, A. N. et al. Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival. J. Cell Biol. 206, 735–749 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Littlefield, O. & Nelson, H. C. A new use for the 'wing' of the 'winged' helix–turn–helix motif in the HSF–DNA cocrystal. Nat. Struct. Biol. 6, 464–470 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Neudegger, T., Verghese, J., Hayer-Hartl, M., Hartl, F. U. & Bracher, A. Structure of human heat-shock transcription factor 1 in complex with DNA. Nat. Struct. Mol. Biol. 23, 140–146 (2016). This study deciphered the structure of the human HSF1 DBD, elucidating key features of HSF1 topology and a new model for the HSF1–DNA interaction.

    Article  CAS  PubMed  Google Scholar 

  29. Fujimoto, M. et al. RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. Mol. Cell 48, 182–194 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Xu, Y. M., Huang, D. Y., Chiu, J. F. & Lau, A. T. Post-translational modification of human heat shock factors and their functions: a recent update by proteomic approach. J. Proteome Res. 11, 2625–2634 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Westerheide, S. D. et al. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063–1066 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raychaudhuri, S. et al. Interplay of acetyltransferase EP300 and the proteasome system in regulating heat shock transcription factor 1. Cell 156, 975–985 (2014). A key role for acetylation in regulating HSF1 degradation.

    Article  CAS  PubMed  Google Scholar 

  33. Carnemolla, A. et al. Contesting the dogma of an age-related heat shock response impairment: implications for cardiac-specific age-related disorders. Hum. Mol. Genet. 23, 3641–3656 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, Q., Xiao, H. & Isobe, K. Histone acetyltransferase activities of cAMP-regulated enhancer-binding protein and p300 in tissues of fetal, young, and old mice. J. Gerontol. A Biol. Sci. Med. Sci. 57, B93–98 (2002).

    Article  PubMed  Google Scholar 

  35. Yang, J., Oza, J., Bridges, K., Chen, K. Y. & Liu, A. Y. Neural differentiation and the attenuated heat shock response. Brain Res. 1203, 39–50 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, D. J. et al. SIRT1 knockdown promotes neural differentiation and attenuates the heat shock response. J. Cell. Physiol. 229, 1224–1235 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Zelin, E., Zhang, Y., Toogun, O. A., Zhong, S. & Freeman, B. C. The p23 molecular chaperone and GCN5 acetylase jointly modulate protein–DNA dynamics and open chromatin status. Mol. Cell 48, 459–470 (2012). This study demonstrated how the chaperone p23 cooperates with the acetyltransferase GCN5 to modulate HSF1 genomic occupancy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zelin, E. & Freeman, B. C. Lysine deacetylases regulate the heat shock response including the age-associated impairment of HSF1. J. Mol. Biol. 427, 1644–1654 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Budzyn´ski, M. A., Puustinen, M. C., Joutsen, J. & Sistonen, L. Uncoupling stress-inducible phosphorylation of heat shock factor 1 from its activation. Mol. Cell. Biol. 35, 2530–2540 (2015).

    Article  CAS  Google Scholar 

  40. Kourtis, N. et al. FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. Nat. Cell Biol. 17, 322–332 (2015). High levels of HSF1 drive cancer survival and metastasis. This work demonstrated that, in some cancers, HSF1 levels are stabilized by loss of the FBXW7 F box protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dai, S. et al. Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK. EMBO J. 34, 275–293 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Jin, X., Moskophidis, D. & Mivechi, N. F. Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab. 14, 91–103 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hendriks, I. A. et al. Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. 24, 325–336 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Anckar, J. et al. Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol. Cell. Biol. 26, 955–964 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hahn, J. S., Hu, Z., Thiele, D. J. & Iyer, V. R. Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol. Cell. Biol. 24, 5249–5256 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem. Soc. Trans. 39, 1–13 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Hahn, J. S. & Thiele, D. J. Activation of the Saccharomyces cerevisiae heat shock transcription factor under glucose starvation conditions by Snf1 protein kinase. J. Biol. Chem. 279, 5169–5176 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Yan, L. J. et al. Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage. EMBO J. 21, 5164–5172 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tsunemi, T. et al. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4, 142ra197 (2012).

    Article  CAS  Google Scholar 

  50. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic co-activator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Bagattin, A., Hugendubler, L. & Mueller, E. Transcriptional co-activator PGC-1α promotes peroxisomal remodelling and biogenesis. Proc. Natl Acad. Sci. USA 107, 20376–20381 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Weydt, P. et al. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration. Cell Metab. 4, 349–362 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. LeBleu, V. S. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ma, X. et al. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1–PGC1α transcriptional axis. Cell Metab. 22, 695–708 (2015). This study identified a role for HSF1 in metabolic regulation through its activation of PGC1α.

    Article  CAS  PubMed  Google Scholar 

  55. Xu, L., Ma, X., Bagattin, A. & Mueller, E. The transcriptional coactivator PGC1α protects against hyperthermic stress via cooperation with the heat shock factor HSF1. Cell Death Dis. 7, e2102 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Minsky, N. & Roeder, R. G. Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α. Proc. Natl Acad. Sci. USA 112, E5669–5678 (2015). This work demonstrates a direct interaction between HSF1 and PGC1α in metabolic regulation.

    Article  CAS  PubMed  Google Scholar 

  57. El Fatimy, R. et al. Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome. EMBO Mol. Med. 6, 1043–1061 (2014). This work identifies a role for HSF2 in neuronal migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Homma, S. et al. Demyelination, astrogliosis, and accumulation of ubiquitinated proteins, hallmarks of CNS disease in hsf1-deficient mice. J. Neurosci. 27, 7974–7986 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ingenwerth, M., Estrada, V., Stahr, A., Müller, H. W. & von Gall, C. HSF1-deficiency affects gait coordination and cerebellar calbindin levels. Behav. Brain Res. 310, 103–108 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Uchida, S. et al. Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1. Proc. Natl Acad. Sci. USA 108, 1681–1686 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Hooper, P. L., Durham, H. D., Török, Z., Crul, T. & Vígh, L. The central role of heat shock factor 1 in synaptic fidelity and memory consolidation. Cell Stress Chaperones 21, 745–753 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Neef, D. W., Jaeger, A. M. & Thiele, D. J. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat. Rev. Drug Discov. 10, 930–944 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Havel, L. S., Li, S. & Li, X. J. Nuclear accumulation of polyglutamine disease proteins and neuropathology. Mol. Brain 2, 21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hay, D. G. et al. Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet. 13, 1389–1405 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Labbadia, J. et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J. Clin. Invest. 121, 3306–3319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chafekar, S. M. & Duennwald, M. L. Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS ONE 7, e37929 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hodges, A. et al. Regional and cellular gene expression changes in human Huntington's disease brain. Hum. Mol. Genet. 15, 965–977 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Labbadia, J. et al. Suppression of protein aggregation by chaperone modification of high molecular weight complexes. Brain 135, 1180–1196 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kampinga, H. H. & Bergink, S. Heat shock proteins as potential targets for protective strategies in neurodegeneration. Lancet Neurol. 15, 748–759 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Kakkar, V. et al. The S/T-rich motif in the DNAJB6 chaperone delays polyglutamine aggregation and the onset of disease in a mouse model. Mol. Cell. 62, 272–283 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Hayashida, N. et al. Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT. EMBO J. 29, 3459–3469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fujimoto, M. et al. Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J. Biol. Chem. 280, 34908–34916 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Kondo, N. et al. Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration. Nat. Commun. 4, 1405 (2013). This work demonstrates that HSF1 has a key role in reducing the extent and tissue distribution of protein aggregation in a polyQ neurodegenerative disease mouse model.

    Article  CAS  PubMed  Google Scholar 

  74. Riva, L. et al. Poly-glutamine expanded huntingtin dramatically alters the genome wide binding of HSF1. J. Huntingtons. Dis. 1, 33–45 (2012). This work demonstrates the genome-wide dysregulation of HSF1 in Huntington disease.

    PubMed  PubMed Central  Google Scholar 

  75. Trinklein, N. D., Murray, J. I., Hartman, S. J., Botstein, D. & Myers, R. M. The role of heat shock transcription factor 1 in the genome-wide regulation of the mammalian heat shock response. Mol. Biol. Cell 15, 1254–1261 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Maheshwari, M. et al. Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease. Hum. Mol. Genet. 23, 2737–2751 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Li, L., Saegusa, H. & Tanabe, T. Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6. Genes Cells 14, 1253–1269 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Batista-Nascimento, L., Neef, D. W., Liu, P. C., Rodrigues-Pousada, C. & Thiele, D. J. Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast. PLoS ONE 6, e15976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shinkawa, T. et al. Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation. Mol. Biol. Cell 22, 3571–3583 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Liangliang, X. et al. Dominant-positive HSF1 decreases α-synuclein level and α-synuclein-induced toxicity. Mol. Biol. Rep. 37, 1875–1881 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Lee, G. et al. Casein kinase II-mediated phosphorylation regulates α-synuclein/synphilin-1 interaction and inclusion body formation. J. Biol. Chem. 279, 6834–6839 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Dzamko, N., Zhou, J., Huang, Y. & Halliday, G. M. Parkinson's disease-implicated kinases in the brain; insights into disease pathogenesis. Front. Mol. Neurosci. 7, 57 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mavroudis, I. A. et al. Morphological changes of the human Purkinje cells and deposition of neuritic plaques and neurofibrillary tangles on the cerebellar cortex of Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen. 25, 585–591 (2010).

    Article  PubMed  Google Scholar 

  85. Chen, Y. et al. Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment. J. Neurosci. 34, 2464–2470 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bobkova, N. V. et al. Therapeutic effect of exogenous Hsp70 in mouse models of Alzheimer's disease. J. Alzheimers Dis. 38, 425–435 (2014).

    Article  PubMed  Google Scholar 

  87. Pierce, A. et al. Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer's-like deficits in mice modeling the disease. J. Neurochem. 124, 880–893 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Masliah, E. et al. Casein kinase II alteration precedes tau accumulation in tangle formation. Am. J. Pathol. 140, 263–268 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Rosenberger, A. F. et al. Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer's disease pathology. J. Neuroinflamm. 13, 4 (2016).

    Article  CAS  Google Scholar 

  90. Greenwood, J. A., Scott, C. W., Spreen, R. C., Caputo, C. B. & Johnson, G. V. Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor. J. Biol. Chem. 269, 4373–4380 (1994).

    CAS  PubMed  Google Scholar 

  91. Lin, P. Y. et al. Heat shock factor 1 over-expression protects against exposure of hydrophobic residues on mutant SOD1 and early mortality in a mouse model of amyotrophic lateral sclerosis. Mol. Neurodegener. 8, 43 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jung, M. K. et al. Expression of taurine transporter (TauT) is modulated by heat shock factor 1 (HSF1) in motor neurons of ALS. Mol. Neurobiol. 47, 699–710 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Batulan, Z. et al. High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J. Neurosci. 23, 5789–5798 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen, H. J. et al. The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain 139, 1417–1432 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Watanabe, S. et al. SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system. Mol. Brain 7, 62 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Carlomagno, Y. et al. Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins. PLoS ONE 9, e90452 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Herman, A. M., Khandelwal, P. J., Stanczyk, B. B., Rebeck, G. W. & Moussa, C. E. β-Amyloid triggers ALS-associated TDP-43 pathology in AD models. Brain Res. 1386, 191–199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dai, C. & Sampson, S. B. HSF1: guardian of proteostasis in cancer. Trends Cell Biol. 26, 17–28 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Björk, J. K. et al. Heat-shock factor 2 is a suppressor of prostate cancer invasion. Oncogene 35, 1770–1784 (2016). HSF2 has a role in tumour suppression by altering gene expression profiles associated with cell differentiation and invasion.

    Article  CAS  PubMed  Google Scholar 

  100. Meng, L., Gabai, V. L. & Sherman, M. Y. Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis. Oncogene 29, 5204–5213 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Min, J. N., Huang, L., Zimonjic, D. B., Moskophidis, D. & Mivechi, N. F. Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors. Oncogene 26, 5086–5097 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Xi, C., Hu, Y., Buckhaults, P., Moskophidis, D. & Mivechi, N. F. Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J. Biol. Chem. 287, 35646–35657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dai, C. et al. Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J. Clin. Invest. 122, 3742–3754 (2012). This work places HSF1 downstream of cancer signalling pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhao, Y. H. et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 28, 3689–3701 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Tang, Z. et al. MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell 160, 729–744 (2015). This study demonstrates a role for HSF1 in protecting cancer cells from proteomic instability, suggesting that HSF1 is a key target for cancer therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Ciocca, D. R., Arrigo, A. P. & Calderwood, S. K. Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch. Toxicol. 87, 19–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Chou, S. D., Murshid, A., Eguchi, T., Gong, J. & Calderwood, S. K. HSF1 regulation of β-catenin in mammary cancer cells through control of HuR/elavL1 expression. Oncogene 34, 2178–2188 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Gabai, V. L. et al. Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. Mol. Cell. Biol. 32, 929–940 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Su, K. H. & Dai, C. Protein quantity–quality balance licenses growth. Cell Cycle 15, 3155–3156 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Su, K. H. et al. HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat. Cell Biol. 18, 527–539 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhong, Y. H., Cheng, H. Z., Peng, H., Tang, S. C. & Wang, P. Heat shock factor 2 is associated with the occurrence of lung cancer by enhancing the expression of heat shock proteins. Oncol. Lett. 12, 5106–5112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Loison, F. et al. Up-regulation of the clusterin gene after proteotoxic stress: implication of HSF1–HSF2 heterocomplexes. Biochem. J. 395, 223–231 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sandqvist, A. et al. Heterotrimerization of heat-shock factors 1 and 2 provides a transcriptional switch in response to distinct stimuli. Mol. Biol. Cell 20, 1340–1347 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Santagata, S. et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341, 1238303 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Fujimoto, M. & Nakai, A. The heat shock factor family and adaptation to proteotoxic stress. FEBS J. 277, 4112–4125 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Goodson, M. L., Park-Sarge, O. K. & Sarge, K. D. Tissue-dependent expression of heat shock factor 2 isoforms with distinct transcriptional activities. Mol. Cell. Biol. 15, 5288–5293 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fujimoto, M. et al. Analysis of HSF4 binding regions reveals its necessity for gene regulation during development and heat shock response in mouse lenses. J. Biol. Chem. 283, 29961–29970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fujimoto, M. et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 23, 4297–4306 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nakai, A. et al. HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Mol. Cell. Biol. 17, 469–481 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fujimoto, M. et al. A novel mouse HSF3 has the potential to activate nonclassical heat-shock genes during heat shock. Mol. Biol. Cell 21, 106–116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tessari, A. et al. Characterization of HSFY, a novel AZFb gene on the Y chromosome with a possible role in human spermatogenesis. Mol. Hum. Reprod. 10, 253–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Wan, Z. et al. Evidence for the role of AMPK in regulating PGC-1α expression and mitochondrial proteins in mouse epididymal adipose tissue. Obes. (Silver Spring) 22, 730–738 (2014).

    Article  CAS  Google Scholar 

  125. Runne, H. et al. Dysregulation of gene expression in primary neuron models of Huntington's disease shows that polyglutamine-related effects on the striatal transcriptome may not be dependent on brain circuitry. J. Neurosci. 28, 9723–9731 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Guettouche, T., Boellmann, F., Lane, W. S. & Voellmy, R. Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress. BMC Biochem. 6, 4 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Asano, Y. et al. IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis. Sci. Rep. 6, 19174 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Olsen, J. V. et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. 3, ra3 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Soncin, F. et al. Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2. Biochem. Biophys. Res. Commun. 303, 700–706 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Calderwood, S. K. et al. Signal transduction pathways leading to heat shock transcription. Sign. Transduct. Insights 2, 13–24 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Holmberg, C. I. et al. Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J. 20, 3800–3810 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hietakangas, V. et al. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1. Mol. Cell. Biol. 23, 2953–2968 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hietakangas, V. et al. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc. Natl Acad. Sci. USA 103, 45–50 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Chu, B., Zhong, R., Soncin, F., Stevenson, M. A. & Calderwood, S. K. Transcriptional activity of heat shock factor 1 at 37 °C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Cα and Cζ. J. Biol. Chem. 273, 18640–18646 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Murshid, A. et al. Protein kinase A binds and activates heat shock factor 1. PLoS ONE 5, e13830 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chou, S. D., Prince, T., Gong, J. & Calderwood, S. K. mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS ONE 7, e39679 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sourbier, C. et al. Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell 23, 228–237 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Tan, K. et al. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat. Commun. 6, 6580 (2015). The mitochondrial SSBP1 DNA replication factor is re-localized in response to stress to interact with nuclear HSF1, potentiating the expression of a network of stress protective genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

E.T.B. is supported by a Predoctoral Fellowship from the US National Institutes of Health (F31 GM119375-02). R.G.-P. is supported by a Postdoctoral Fellowship from the Huntington's Disease Society of America Human Biology Project. The authors acknowledge Alex Jaeger for assistance with Figure 2 and the Reviewers for excellent comments and suggestions.

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Authors and Affiliations

Authors

Contributions

R.G.-P., E.T.B. and D.J.T. contributed equally to researching data for the article, discussion of content and writing and reviewing the manuscript before submission.

Corresponding author

Correspondence to Dennis J. Thiele.

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Competing interests

Dennis J. Thiele is on the Scientific Advisory Board of Chaperone Therapeutics, Inc., and holds equity in the company. Rocio Gomez-Pastor and Eileen Malloy declare no competing interests.

Supplementary information

Supplementary information S1

MicroRNAs and long non-coding RNAs in the regulation of HSFs (PDF 184 kb)

Supplementary information S2

Splicing isoforms of HSFs (PDF 111 kb)

Supplementary information S3

Post-translational modifications of HSFs (PDF 226 kb)

Supplementary information S4

HSFs and brain function (PDF 127 kb)

Supplementary information S5

HSF1 and HSF2 and the cell cycle (PDF 108 kb)

Supplementary information S6

List of genes differentially regulated by HSF1 in Cancer and in Huntington disease (see Fig. 5b) (PDF 85 kb)

PowerPoint slides

Glossary

Winged helix–turn–helix

(wHTH). Structural feature of a protein containing α-helices, β-sheets and loops arranged to form a helix–turn–helix DNA-binding motif with a wing domain.

Transactivation

Activation of gene expression by transcription factors.

Chaperonin

Multi-subunit protein folding machines found from bacteria to humans that fold proteins in an ATP-dependent manner.

Valosin-containing protein

(p97/VCP). A multitasking, chaperone-like AAA ATPase involved in protein ubiquitylation.

Aneuploidy

An abnormal number of chromosomes.

Genomic instability

The acquisition of insertions, deletions or rearrangements in chromosomes or loss of chromosomes.

Wing domain

A structural feature in a winged helix–turn–helix domain typically composed of loops that come together to form a butterfly-like, 'wing' protrusion, typically in contact with the DNA backbone.

Focal adhesions

Functional points of contact that facilitate signalling in response to stimuli such as force.

GTPases

Guanine nucleotide-hydrolysing proteins that function in cellular signalling, protein translation, vesicular trafficking and other processes.

Lewy bodies

Protein aggregates in Parkinson disease and other dementias.

Substantia nigra

Midbrain structure of basal ganglia that has an important role in movement and reward function.

Purkinje cells

Large GABAergic neurons in the cerebellar cortex with a large number of dendritic spines, which are small protrusions that receive axonal input.

Astrocytes

Supporting glial cells in the brain and spinal cord that contribute to the function and health of other cells in the central nervous system.

Oncogenic RAS

RAS is a family of related small GTPases involved in signal transduction pathways. RAS mutations are the most common cancer-associated mutations.

Nuclear factor-κB

(NF-κB). A protein complex that controls the expression of genes involved in inflammation and a range of other functions.

Mechanistic target of rapamycin complex 1

(mTORC1). Controls protein synthesis and senses the cellular energy, nutrient and redox balance status.

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Gomez-Pastor, R., Burchfiel, E. & Thiele, D. Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol 19, 4–19 (2018). https://doi.org/10.1038/nrm.2017.73

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