Heat Shock Response
Transcriptional Regulation of Heat Shock Response
Group Leader
Lea Sistonen
Professor of Cell and Molecular Biology
Department of Biology
Åbo Akademi University
lea.sistonen (at) btk.fi
Contact Information
Turku Centre for Biotechnology
P.O.Box 123, BioCity
Street: Tykistökatu 6B
Turku FIN-20521, Finland
+358-2-333-8028 (Lea Sistonen)
+358-2-333-8000 (Attn. Lea Sistonen)
Please look at the personal member's pages
- Lea Sistonen
- Johanna Ahlskog
- Heidi Bergman
- Johanna Björk
- Henri Blomster
- Marek Budzynski
- Alexandra Elsing
- Eva Henriksson
- Helena Saarento
- Anton Sandqvist
- Jenny Siimes
- Anniina Vihervaara
- Malin Åkerfelt
Project
Expression and Regulation of the Heat Shock Transcription Factors HSF1 and HSF2 (see below)
Signal Transduction in Cell Stress and Receptor-Mediated Apoptosis (together with John Eriksson, Turku Centre for Biotechnology)
Description of the Project
Activation of the heat shock transcription factor 1 (HSF1) is a multi-step process, including trimerization, acquisition of DNA- binding activity, further modifications (e.g. hyperphosphorylation), and transcriptional activation of target genes.
This research project aims at understanding the molecular mechanisms by which cells and whole organisms respond to heat stress and other protein-damaging insults, leading to a dramatic reprogramming of gene expression patterns essential for the maintenance of protein homeostasis or proteostasis. The heat shock response is a fundamental protective mechanism that is characterized by increased expression of heat shock proteins (Hsps) under proteotoxic conditions, such as elevated temperatures. Hsps function as molecular chaperones that are essential for folding of nascent polypeptides and for repair or triage of damaged proteins, promoting cellular viability under conditions that would otherwise be lethal. Besides environmental stress, Hsps are intimately involved in many diseases, such as neurodegeneration, metabolic disorders, ischemia-reperfusion injury and cancer. There is increasing interest in the molecular basis of the heat shock response and in discovering small molecules and other therapies to modulate the heat shock response.
Our main goal is to elucidate the expression and activity of two heat shock transcription factors, HSF1 and HSF2, which belong to the HSF family consisting of four members (HSF1-4) in mammals and other vertebrates. HSF1 is the major stress-responsive factor that cannot be replaced by any other HSF, whereas HSF2 was originally considered refractory to stress but important for development. We have, however, found a structural and functional interplay between HSF1 and HSF2 (Alastalo et al. 2003, Östling et al. 2007, Sandqvist et al. 2009, see Figure below), which has opened up a completely new dimension of HSFs, thereby challenging the old hypothesis of the independent or unique roles of HSF1 and HSF2. This is particularly important when considering HSF1 as a therapeutic target for diseases where HSF-mediated gene expression is abnormal.
In addition to the hypothesis-driven research, based on either the previously obtained results in our own laboratory or the results described in the literature, we have also undertaken a number of unbiased strategies to search for novel target genes for HSF1 and HSF2, especially in the context of development and differentiation (e.g. corticogenesis and spermatogenesis). Using high-resolution chromatin immunoprecipitation on promoter microarray (ChIP-chip) on mouse testis, which to our knowledge was the first attempt to apply this method to a mammalian tissue instead of cells grown in culture, we identified a multitude of HSF2 target genes. Analysis of the chromosomal distribution of HSF2 occupancy led to a surprising discovery that HSF2 regulates the Y-chromosomal genes critical for male germ cell differentiation and sperm quality (Åkerfelt et al. 2008). This project is now rapidly expanding with emphasis on HSFs in male reproductive biology and the role of HSF2 in testicular cancers.
HSFs are subjected to extensive post-translational modifications (PTMs), such as acetylation, phosphorylation, sumoylation and ubiquitylation. We are interested in establishing the impact of the PTMs in the context of regulation of specific target genes. The project is based on our discovery of phosphorylation-dependent sumoylation of HSF1 repressing the stress-inducible transcrip of hsp genes (Hietakangas et al. 2003, 2006). We will determine the functional hirerachy of PTMs and possible switches between acetylation and sumoylation, which occur on the same lysine residues. In collaboration with Rick Morimoto (Northwestern University, Evanston, USA), we have found that HSF1 activity is enhanced by the deacetylase and longevity factor SIRT1, a member of the sirtuin family (Westerheide et al. 2009). We will expand the studies from cultured cell to in vivo models to examine whether the relationship between SIRT1 and HSF1 has an impact in tissues in an organism at different stages of development and aging. A consistent observation in previous studies has been an aging-related decline of the heat shock response, which could be due to our finding that SIRT1 controls HSF1 activity. Beyond the fields of cell stress and HSF biology, our research is of general interest in revealing the regulatory mechanisms of transcription factors.
Schematic illustration of HSF1-HSF2 heterotrimerization as a mechanism integrating HSF activity in cell stress and development (Sandqvist et.al. 2009). HSF1 and HSF2 are indicated as 1 (green) and 2 (red), respectively. Upon stress stimuli, HSF1 is activated, leading to formation of HSF1-HSF2 heterotrimers. Stress-induced HSF activity is regulated through HSF1-HSF2 heterotrimerization, a mechanism that probably provides also temporal regulation, since heat stress diminishes HSF2 levels, thereby restricting heterotrimerization through limited availability of HSF2. During development, HSF2 levels are increased at certain stages and in a tissue-specific manner, leading to activation of HSF2. Elevated HSF2 expression in turn induces HSF1-HSF2 hetero-trimerization, highlighting the integrating role for the formation of HSF1-HSF2 heterotrimers in response to distinct stimuli.
Funding
The Academy of Finland, Sigrid Jusélius Foundation, The Finnish Cancer Organisations, The Borg Foundation (Åbo Akademi University), Center of Excellence Program of Åbo Akademi University
Selected Publications (* equal contribution)
Original Articles
Holmberg C.I., Hietakangas V., Mikhailov A., Rantanen J.O, Kallio M., Meinander A., Hellman J., Morrice N., MacKintosh C., Morimoto R.I., Eriksson J.E. & Sistonen L. 2001. Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1. EMBO J. 20: 3800-3810. PubMed
Kallio M.*, Chang Y.*, Manuel M., Alastalo T-P., Rallu M., Gitton Y., Pirkkala L., Loones M-T., Paslaru L., Larney S., Hiard S., Morange M., Sistonen L. & Mezger V. 2002. Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J. 21: 2591-2601. PubMed
Hietakangas V., Ahlskog J.K., Jakobsson A.M., Hellesuo M., Sahlberg N.M., Holmberg C.I., Mikhailov A., Palvimo J.J., Pirkkala L. & Sistonen L. 2003. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO-1 modification of heat shock factor 1. Mol. Cell. Biol. 23: 2953-2968. PubMed
Alastalo T-P., Hellesuo M., Sandqvist A., Hietakangas V., Kallio M. & Sistonen L. 2003. Formation of nuclear stress granules involves HSF2 and coincides with the nucleolar localization of Hsp70. J. Cell Sci. 116: 3557-3570. PubMed
Hietakangas V.*, Anckar J.*, Blomster H.A., Fujimoto M., Palvimo J.J., Nakai A. & Sistonen L. 2006. PDSM, a motif for phosphorylation-dependent SUMO modification. Proc. Natl. Acad. Sci. USA 103: 45-50. PubMed
Anckar J.*, Hietakangas V.*, Denessiouk K., Thiele D.J., Johnson M.S. & Sistonen L. 2006. Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol. Cell. Biol. 26: 955-964. PubMed
Chang Y.*, Östling P.*, Åkerfelt M., Trouillet D., Rallu M., Gitton Y., El Fatimy R., Fardeau V., Le Crom S., Morange M., Sistonen L. & Mezger V. 2006. Role of heat shock factor 2 in cerebral cortex formation and as a regulator of p35 expression. Genes Dev. 20: 836-847. PubMed
Meinander A., Söderström T.S., Kaunisto A., Poukkula M., Sistonen L. & Eriksson J.E. 2007. Fever-like hyperthermia controls T lymphocyte persistence by inducing degradation of cellular FLIPshort. J. Immunol. 178: 3944-3953. PubMed
Östling P.*, Björk J.K.*, Roos-Mattjus P., Mezger V. & Sistonen L. 2007. HSF2 contributes to inducible expression of hsp genes through interplay with HSF1. J. Biol. Chem. 282: 7077-7086. PubMed
Åkerfelt M.*, Henriksson E.*, Laiho A., Vihervaara A., Rautoma K., Kotaja N. & Sistonen L. 2008. Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2. Proc. Natl. Acad. Sci. USA 105: 11224-11229. PubMed
Westerheide S.D.*, Anckar J.*. Stevens S.M.Jr., Sistonen L. & Morimoto R.I. 2009. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323: 1063-1066. PubMed
Sandqvist A. Björk J.K., Åkerfelt M., Chitikova Z., Grichine A., Vourc'h C., Jolly C., Salminen T.A., Nymalm Y. & Sistonen L. 2009. Heterotrimerization of heat-shock factors 1 and 2 provides a transcriptional swithch in response to distinct stimuli. Mol. Biol. Cell 20: 1340-1347. PubMed
Blomster H.A., Hietakangas V., Wu J., Kouvonen P., Hautaniemi S. & Sistonen L. 2009. Novel proteomics strategy brings insight into the prevalence of SUMO-2 target sites. Mol. Cell. Proteomics 8: 1382-1390. PubMed
Blomster H.A., Imanishi S.Y., Siimes J., Kastu J., Morrice N.A., Eriksson J.E., Sistonen L. 2010. In vivo identification of sumoylation sites by a signature tag and cysteine-targeted affinity purification. J Biol Chem. 285:19324-19329. PubMed
Björk J.K., Sandqvist A., Elsing A.N., Kotaja N., Sistonen L. 2010. miR-18, a member of Oncomir-1, targets heat shock transcription factor 2 in spermatogenesis. Development, in press. PubMed
Åkerfelt M., Vihervaara A., Laiho A., Conter A., Christians E.S., Sistonen L., Henriksson E. 2010. Heat shock transcription factor 1 localizes to the sex chromatin during meiotic repression. J Biol Chem, in press. PubMed
Review Articles
Pirkkala L., Nykänen P. & Sistonen L. 2001. Roles of the heat shock transcription factors in regulation of the stress response and beyond. FASEB J. 15: 1118-1131. PubMed
Holmberg C.I., Tran S.E.F., Eriksson J.E. & Sistonen L. 2002. Multisite phosphorylation provides sophisticated regulation of transcription factors. Trends Biochem. Sci. 27: 619-627. PubMed
Anckar J. & Sistonen L. 2007. Heat shock factor 1 as a coordinator of stress and developmental pathways. In: “Molecular Aspects of the Stress Response: Chaperones, Membranes and Networks”, eds. P. Csermely and L. Vigh. Advances in Experimental Medicine and Biology, vol. 594. Landes Bioscience and Springer Science+Business Media, Austin, Texas, pp. 78-88. PubMed
Åkerfelt M., Trouillet D., Mezger V. & Sistonen L. 2007. Heat shock factors at a crossroad between stress and development. Ann. N.Y. Acad. Sci. 1113: 15-27. PubMed
Anckar J. & Sistonen L. 2007. SUMO – getting it on. Biochem. Soc. Trans. 35: 1409-1413. PubMed
Åkerfelt M., Morimoto R.I., Sistonen L. 2010. Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11: 545-555. PubMed