Mechanisms tailoring the expression of heat shock proteins to proteostasis challenges
2022; Elsevier BV; Volume: 298; Issue: 5 Linguagem: Inglês
10.1016/j.jbc.2022.101796
ISSN1083-351X
AutoresLokha R. Alagar Boopathy, Suleima Jacob‐Tomas, Célia Alecki, Mariá Vera,
Tópico(s)Protein Structure and Dynamics
ResumoAll cells possess an internal stress response to cope with environmental and pathophysiological challenges. Upon stress, cells reprogram their molecular functions to activate a survival mechanism known as the heat shock response, which mediates the rapid induction of molecular chaperones such as the heat shock proteins (HSPs). This potent production overcomes the general suppression of gene expression and results in high levels of HSPs to subsequently refold or degrade misfolded proteins. Once the damage or stress is repaired or removed, cells terminate the production of HSPs and resume regular functions. Thus, fulfillment of the stress response requires swift and robust coordination between stress response activation and completion that is determined by the status of the cell. In recent years, single-cell fluorescence microscopy techniques have begun to be used in unravelling HSP-gene expression pathways, from DNA transcription to mRNA degradation. In this review, we will address the molecular mechanisms in different organisms and cell types that coordinate the expression of HSPs with signaling networks that act to reprogram gene transcription, mRNA translation, and decay and ensure protein quality control. All cells possess an internal stress response to cope with environmental and pathophysiological challenges. Upon stress, cells reprogram their molecular functions to activate a survival mechanism known as the heat shock response, which mediates the rapid induction of molecular chaperones such as the heat shock proteins (HSPs). This potent production overcomes the general suppression of gene expression and results in high levels of HSPs to subsequently refold or degrade misfolded proteins. Once the damage or stress is repaired or removed, cells terminate the production of HSPs and resume regular functions. Thus, fulfillment of the stress response requires swift and robust coordination between stress response activation and completion that is determined by the status of the cell. In recent years, single-cell fluorescence microscopy techniques have begun to be used in unravelling HSP-gene expression pathways, from DNA transcription to mRNA degradation. In this review, we will address the molecular mechanisms in different organisms and cell types that coordinate the expression of HSPs with signaling networks that act to reprogram gene transcription, mRNA translation, and decay and ensure protein quality control. For organisms to grow and function properly, they must maintain specific internal cellular conditions that allow proteins to acquire their functional conformations and cells to achieve protein homeostasis (proteostasis) (1Gasch A.P. Spellman P.T. Kao C.M. Carmel-Harel O. Eisen M.B. Storz G. Botstein D. Brown P.O. Genomic expression programs in the response of yeast cells to environmental changes.Mol. Biol. Cell. 2000; 11: 4241-4257Crossref PubMed Google Scholar). Maintaining proteostasis becomes critical when facing abrupt changes in the external conditions, such as an increase in temperature, which can lead to protein misfolding and aggregation, and consequently, cellular dysfunction (2van Oosten-Hawle P. Morimoto R.I. Organismal proteostasis: Role of cell-nonautonomous regulation and transcellular chaperone signaling.Genes Dev. 2014; 28: 1533-1543Crossref PubMed Scopus (60) Google Scholar). Thus, organisms must sense, rapidly respond, and adapt to new environmental conditions for survival. Organisms from bacteria to mammals have evolved similar and varying stress responses to cope with protein misfolding and maintain proteostasis successfully. Some of these strategies include modulations of signaling cascades, changes in transcriptional programs, and regulation of translation, posttranslational modifications, and the dynamic assembly of RNA and protein condensates (ribonucleoprotein [RNP] granules) through liquid–liquid phase separation (1Gasch A.P. Spellman P.T. Kao C.M. Carmel-Harel O. Eisen M.B. Storz G. Botstein D. Brown P.O. Genomic expression programs in the response of yeast cells to environmental changes.Mol. Biol. Cell. 2000; 11: 4241-4257Crossref PubMed Google Scholar, 3de la Fuente M. Valera S. Martínez-Guitarte J.L. ncRNAs and thermoregulation: A view in prokaryotes and eukaryotes.FEBS Lett. 2012; 586: 4061-4069Crossref PubMed Scopus (0) Google Scholar, 4Protter D.S.W. Parker R. Principles and properties of stress granules.Trends Cell Biol. 2016; 26: 668-679Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 5Pohl C. Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy.Science. 2019; 366: 818-822Crossref PubMed Scopus (267) Google Scholar, 6Pomatto L.C.D. Davies K.J.A. The role of declining adaptive homeostasis in ageing.J. Physiol. 2017; 595: 7275-7309Crossref PubMed Scopus (76) Google Scholar, 7Yasuda S. Tsuchiya H. Kaiho A. Guo Q. Ikeuchi K. Endo A. Arai N. Ohtake F. Murata S. Inada T. Baumeister W. Fernández-Busnadiego R. Tanaka K. Saeki Y. Stress- and ubiquitylation-dependent phase separation of the proteasome.Nature. 2020; 578: 296-300Crossref PubMed Scopus (84) Google Scholar). Several of these molecular mechanisms converge to sustain proteostasis in response to sudden and acute changes in environmental conditions. Increases in the environmental temperature is a universal proteostasis challenge encountered by most organisms. For historical reasons, thermal stress has been used as a paradigm to study the stress response. Nowadays, these studies have an additional relevance due to the increased exposure of organisms to heatwaves derived from climate change (8Tomanek L. The importance of physiological limits in determining biogeographical range shifts due to global climate change: The heat-shock response.Physiol. Biochem. Zool. 2008; 81: 709-717Crossref PubMed Scopus (114) Google Scholar, 9Kassahn K.S. Crozier R.H. Pörtner H.O. Caley M.J. Animal performance and stress: Responses and tolerance limits at different levels of biological organisation.Biol. Rev. Camb. Philos. Soc. 2009; 84: 277-292Crossref PubMed Scopus (174) Google Scholar, 10Sengupta P. Garrity P. Sensing temperature.Curr. Biol. 2013; 23: R304-R307Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Increased thermal energy in the cells can result in heat-induced denaturation of proteins and thermally altered metabolic activity leading to an increase in reactive oxygen species, which can damage all biological macromolecules, including proteins (11Somero G.N. The cellular stress response and temperature: Function, regulation, and evolution.J. Exp. Zool A Ecol. Integr. Physiol. 2020; 333: 379-397Crossref PubMed Scopus (44) Google Scholar). Cells cope with an increased load of unfolded and misfolded proteins by modulating the expression of specific molecular chaperones, also known as heat shock proteins (HSPs) (12Parsell D.A. Lindquist S. The function of heat-shock proteins in stress tolerance: Degradation and reactivation of damaged proteins.Annu. Rev. Genet. 1993; 27: 437-496Crossref PubMed Google Scholar, 13Kültz D. Molecular and evolutionary basis OF the cellular stress response.Annu. Rev. Physiol. 2005; 67: 225-257Crossref PubMed Scopus (977) Google Scholar, 14Daugaard M. Rohde M. Jäättelä M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions.FEBS Lett. 2007; 581: 3702-3710Crossref PubMed Scopus (830) Google Scholar, 15Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (295) Google Scholar). The heat shock response (HSR) refers to the activation of the expression of HSPs, and it is the most common and widely studied cell response to thermal stress. HSPs play a central role in the lifecycle of proteins because they promote the folding of nascent polypeptides into their native/functional configurations and prevent protein misfolding and aggregation (12Parsell D.A. Lindquist S. The function of heat-shock proteins in stress tolerance: Degradation and reactivation of damaged proteins.Annu. Rev. Genet. 1993; 27: 437-496Crossref PubMed Google Scholar, 15Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (295) Google Scholar, 16Morimoto R.I. The heat shock response: Systems biology of proteotoxic stress in aging and disease.Cold Spring Harb. Symp. Quant Biol. 2011; 76: 91-99Crossref PubMed Scopus (263) Google Scholar). HSPs also collaborate with the quality control mechanisms, the ubiquitin-proteasome system, and autophagy, to target misfolded proteins and aggregates whose native functional state cannot be recovered for degradation (5Pohl C. Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy.Science. 2019; 366: 818-822Crossref PubMed Scopus (267) Google Scholar, 17Wang Y. Le W.D. Autophagy and ubiquitin-proteasome system.Adv. Exp. Med. Biol. 2019; 1206: 527-550Crossref PubMed Scopus (37) Google Scholar). Given that HSPs are central to the cellular proteostasis network, cells undertake several gene expression adaptations to favor the synthesis of HSPs at the expense of decreasing most cellular functions (Fig. 1). Biochemical and molecular biology approaches highlight the unique regulation of HSP gene expression. The spatiotemporal resolution of such precise regulation is now being uncovered using high-resolution quantitative fluorescence microscopy. Gene expression adaptions during stress act together to protect macromolecules and promptly resume the cytoplasmic and nuclear activities once permissive conditions are restored (3de la Fuente M. Valera S. Martínez-Guitarte J.L. ncRNAs and thermoregulation: A view in prokaryotes and eukaryotes.FEBS Lett. 2012; 586: 4061-4069Crossref PubMed Scopus (0) Google Scholar). The regulation of HSP expression coordinates with other cell protective mechanisms, like the formation of RNP condensates and the activation of the integrated stress response (ISR) to repress translation initiation. The ISR and HSR also coordinate their actions with the unfolded protein response in the endoplasmic reticulum (ER) and the mitochondria to preserve proteostasis across cellular compartments. All organisms ranging from bacteria to plants and mammals have genes encoding for HSPs. HSPs are grouped into families based on an apparent molecular weight (18Jayaraj G.G. Hipp M.S. Hartl F.U. Functional modules of the proteostasis network.Cold Spring Harb. Perspect. Biol. 2020; 12a033951Crossref PubMed Scopus (47) Google Scholar, 19Kampinga H.H. Hageman J. Vos M.J. Kubota H. Tanguay R.M. Bruford E.A. Cheetham M.E. Chen B. Hightower L.E. Guidelines for the nomenclature of the human heat shock proteins.Cell Stress Chaperones. 2009; 14: 105-111Crossref PubMed Scopus (813) Google Scholar). The HSP70 and HSP90 families are the most functionally relevant HSPs in the cell (15Rosenzweig R. Nillegoda N.B. Mayer M.P. Bukau B. The Hsp70 chaperone network.Nat. Rev. Mol. Cell Biol. 2019; 20: 665-680Crossref PubMed Scopus (295) Google Scholar, 20Abisambra J.F. Blair L.J. Hill S.E. Jones J.R. Kraft C. Rogers J. Koren J. Jinwal U.K. Lawson L. Johnson A.G. Wilcock D. O'Leary J.C. Jansen-West K. Muschol M. Golde T.E. et al.Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice.J. Neurosci. 2010; 30: 15374-15382Crossref PubMed Scopus (78) Google Scholar). They are ATP-dependent chaperones that cooperate with small HSPs and HSP110. Cochaperones of the J-domain family of proteins modulate HSP70 activity by accelerating ATP hydrolysis, participating in substrate recognition and substrate folding or refolding (Fig. 2) (21Gamerdinger M. Hajieva P. Kaya A.M. Wolfrum U. Hartl F.U. Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3.EMBO J. 2009; 28: 889-901Crossref PubMed Scopus (385) Google Scholar, 22Kumar P. Ambasta R.K. Veereshwarayya V. Rosen K.M. Kosik K.S. Band H. Mestril R. Patterson C. Querfurth H.W. CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism.Hum. Mol. Genet. 2007; 16: 848-864Crossref PubMed Scopus (0) Google Scholar, 23Lindquist S. The heat-shock response.Annu. Rev. Biochem. 1986; 55: 1151-1191Crossref PubMed Google Scholar, 24Lindquist S. Craig E.A. The heat-shock proteins.Annu. Rev. Genet. 1988; 22: 631-677Crossref PubMed Google Scholar, 25Liu Q. Liang C. Zhou L. Structural and functional analysis of the Hsp70/Hsp40 chaperone system.Protein Sci. 2020; 29: 378-390Crossref PubMed Scopus (28) Google Scholar, 26Petrucelli L. Dickson D. Kehoe K. Taylor J. Snyder H. Grover A. De Lucia M. McGowan E. Lewis J. Prihar G. Kim J. Dillmann W.H. Browne S.E. Hall A. Voellmy R. et al.CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.Hum. Mol. Genet. 2004; 13: 703-714Crossref PubMed Scopus (560) Google Scholar, 27Ritossa F. A new puffing pattern induced by temperature shock and DNP in drosophila.Experientia. 1962; 18: 571-573Crossref Scopus (1424) Google Scholar). HSPs are further categorized as constitutive or inducible based on their steady-state expression levels. The expression of all inducible and some constitutive HSPs is upregulated to some extent upon heat stress. Among them, the inducible HSP70 genes are the fastest and most upregulated (23Lindquist S. The heat-shock response.Annu. Rev. Biochem. 1986; 55: 1151-1191Crossref PubMed Google Scholar, 24Lindquist S. Craig E.A. The heat-shock proteins.Annu. Rev. Genet. 1988; 22: 631-677Crossref PubMed Google Scholar, 27Ritossa F. A new puffing pattern induced by temperature shock and DNP in drosophila.Experientia. 1962; 18: 571-573Crossref Scopus (1424) Google Scholar). Interestingly, they are highly conserved among species having an amino acid similarity of 50% between Homo sapiens and Escherichia coli, while some domains are 96% similar, which highlights its vital role in cell adaption to changing environmental conditions (28Sørensen J.G. Kristensen T.N. Loeschcke V. The evolutionary and ecological role of heat shock proteins: Heat shock proteins.Ecol. Lett. 2003; 6: 1025-1037Crossref Scopus (0) Google Scholar).Figure 2The function of HSC70/HSP70 in retaining the cellular proteostasis. The illustration depicts the significant tasks of the HSP70 chaperone network inside the cell to maintain proteostasis. (Starting from the top left tile) Under nonstress conditions, HSC70 provides cotranslational folding of the nascent polypeptide to obtain native conformation; helps to refold misfolded proteins; transports nascent polypeptide from the cytoplasm to the mitochondria where it is assisted by mitochondrial HSP70 (mtHSP70) and HSP60 to attain functional conformation; involved in protein complex assembly and/or disassembly; and leads specific proteins for their degradation by the lysosome through chaperone-mediated autophagy (236Massey A. Kiffin R. Cuervo A.M. Pathophysiology of chaperone-mediated autophagy.Int. J. Biochem. Cell Biol. 2004; 36: 2420-2434Crossref PubMed Scopus (148) Google Scholar, 237Majeski A.E. Dice J.F. Mechanisms of chaperone-mediated autophagy.Int. J. Biochem. Cell Biol. 2004; 36: 2435-2444Crossref PubMed Scopus (299) Google Scholar). (Continuing bottom left tile) During stress, the lack of HSP70 at the exit of the ribosome tunnel represses the translation at the elongation stage. HSP70 and HSP90 prevent protein aggregation, and HSP70 also resolves stress granules so that the sequestered mRNAs can resume their translation during recovery from stress; targets terminally misfolded protein for proteasomal degradation; and mediates autophagy by autophagosome. HSP, heat shock protein.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In this review, we frame the molecular regulation of the HSR to the context of the gene expression changes undertaken by eukaryotic cells in response to an increase in temperature. We compare the response mounted by different organisms and cell types and suggest new technological approaches to overcome the gap in our knowledge on the HSPs expression. The robust transcriptional induction of genes of the HSP70 family is one of the main and fastest response to heat stress. Their transcriptional induction occurs at the expense of a general transcriptional downregulation of constitutively expressed genes. Most inducible HSP70 genes are short (around 2500 nucleotides) and intronless, and their promoter contains one or more binding sites, known as heat shock elements (HSEs), for the association of the master transcription factor heat shock factor 1 (HSF1) (29Brocchieri L. Conway de Macario E. Macario A.J. hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions.BMC Evol. Biol. 2008; 8: 19Crossref PubMed Scopus (178) Google Scholar). Under physiological conditions, the inducible HSP70 genes are not expressed. However, their loci are neither present in a compact heterochromatin domain nor marked by repressive epigenetic histone modification. The promoter and 3′ end of HSP70 gene is nucleosome-free while its gene body is covered by nucleosomes. The promoter is bound by a paused RNA polymerase II (RNAPII) (30Petesch S.J. Lis J.T. Rapid, transcription-independent loss of nucleosomes over a large chromatin domain at Hsp70 loci.Cell. 2008; 134: 74-84Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). These characteristics prevent the stable transcriptional repression of HSP70 genes and facilitate their prompt activation in response to the binding of HSF1. Under physiological conditions, HSF1 shuttles between the nucleus and cytoplasm, and it is kept as an inactive monomer by constitutive members of HSP90 and HSP70 families. Upon stress, HSF1 is released from HSPs, trimerizes, and localizes in the nucleus where it binds to the HSE, which is comprised of at least three nGAAn repeats organized head to tail in the promoters of genes encoding HSPs and other gene products (31Anckar J. Sistonen L. Regulation of HSF1 function in the heat stress response: Implications in aging and disease.Annu. Rev. Biochem. 2011; 80: 1089-1115Crossref PubMed Scopus (462) Google Scholar, 32Vihervaara A. Sistonen L. HSF1 at a glance.J. Cell Sci. 2014; 127: 261-266Crossref PubMed Scopus (169) Google Scholar) (Fig. 3). HSF1 has three domains, an oligomerization domain next to the DNA binding domain at the N terminus, a trans-activation domain at the C terminus that induces transcription initiation and elongation, and a regulatory domain in the middle that negatively regulates the function of the trans-activation domain in nonstress conditions. By forming a trimer, the affinity of HSF1 for the HSE increases as each HSF1 of the trimer binds to a nGAAn repeat through its DNA binding domain. The binding of HSF1 to HSE is not sufficient to activate transcription and has to be accompanied by extensive posttranslational modifications. HSF1 undergoes hyperphosphorylation of serine and threonine residues that cover up to 90% of the regulatory domain (33Björk J.K. Sistonen L. Regulation of the members of the mammalian heat shock factor family.FEBS J. 2010; 277: 4126-4139Crossref PubMed Scopus (0) Google Scholar, 34Gomez-Pastor R. Burchfiel E.T. Thiele D.J. Regulation of heat shock transcription factors and their roles in physiology and disease.Nat. Rev. Mol. Cell Biol. 2018; 19: 4-19Crossref PubMed Scopus (272) Google Scholar, 35Guettouche T. Boellmann F. Lane W.S. Voellmy R. Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress.BMC Biochem. 2005; 6: 4Crossref PubMed Scopus (222) Google Scholar, 36Nakai A. Molecular basis of HSF regulation.Nat. Struct. Mol. Biol. 2016; 23: 93-95Crossref PubMed Scopus (15) Google Scholar). However, only a few of these phosphorylation sites, like serines 230 or 326, are necessary for the activity of HSF1 (35Guettouche T. Boellmann F. Lane W.S. Voellmy R. Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stress.BMC Biochem. 2005; 6: 4Crossref PubMed Scopus (222) Google Scholar, 37Boellmann F. Guettouche T. Guo Y. Fenna M. Mnayer L. Voellmy R. DAXX interacts with heat shock factor 1 during stress activation and enhances its transcriptional activity.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 4100-4105Crossref PubMed Scopus (70) Google Scholar). Concomitantly, sumo groups that have an inhibitory effect on transcription are removed from HSF1 (38Hietakangas V. Anckar J. Blomster H.A. Fujimoto M. Palvimo J.J. Nakai A. Sistonen L. PDSM, a motif for phosphorylation-dependent SUMO modification.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 45-50Crossref PubMed Scopus (374) Google Scholar). HSF1 acetylation at lysines 116 and 118 favors its transcriptional activity, whereas acetylation at several other lysine residues regulates its nuclear localization and oligomerization (31Anckar J. Sistonen L. Regulation of HSF1 function in the heat stress response: Implications in aging and disease.Annu. Rev. Biochem. 2011; 80: 1089-1115Crossref PubMed Scopus (462) Google Scholar). Acetylation of HSF1 occurs a few hours after heat shock to decrease its DNA affinity and the transcriptional response (39Westerheide S.D. Anckar J. Stevens S.M. Sistonen L. Morimoto R.I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1.Science. 2009; 323: 1063-1066Crossref PubMed Scopus (530) Google Scholar). In summary, HSF1 undergoes extensive posttranslational modifications, which are regulated under various stresses. Although the function of some of these modifications has been identified, the role of many others, as well as the proteins responsible for their regulation, remains to be elucidated. The combination of posttranslational modifications and titration of HSPs by misfolded proteins have been demonstrated to activate HSF1. Recent work in the yeast, Saccharomyces cerevisiae, has allowed building a simple mathematical model that points to the dissociation of HSP70/HSP90 from HSF1 as the first "switch on" step to activate HSP70 transcription, which feedback to HSF1 to switch it off or repress it (40Krakowiak J. Zheng X. Patel N. Feder Z.A. Anandhakumar J. Valerius K. Gross D.S. Khalil A.S. Pincus D. Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response.Elife. 2018; 7e31668Crossref PubMed Scopus (33) Google Scholar, 41Zheng X. Krakowiak J. Patel N. Beyzavi A. Ezike J. Khalil A.S. Pincus D. Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation.Elife. 2016; 5e18638Crossref Scopus (97) Google Scholar). Zheng et al. (41Zheng X. Krakowiak J. Patel N. Beyzavi A. Ezike J. Khalil A.S. Pincus D. Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation.Elife. 2016; 5e18638Crossref Scopus (97) Google Scholar) identified 70 phosphorylation sites on HSF1 upon heat shock and were able to model that these phosphorylations have no effect on HSF1 activation but instead increase its transcriptional activity by favoring its association with the mediator complex. Additionally, the translation factor eEF1A and the noncoding RNA HSR1 are among the factors activating HSF1. They act together to form a nucleoprotein complex with HSF1 and stimulate HSF1 trimerization (42Shamovsky I. Ivannikov M. Kandel E.S. Gershon D. Nudler E. RNA-mediated response to heat shock in mammalian cells.Nature. 2006; 440: 556-560Crossref PubMed Scopus (271) Google Scholar). Following heat shock, HSF1 recruits multiple cofactors to HSE (43Chen Y. Chen J. Yu J. Yang G. Temple E. Harbinski F. Gao H. Wilson C. Pagliarini R. Zhou W. Identification of mixed lineage leukemia 1(MLL1) protein as a coactivator of heat shock factor 1(HSF1) protein in response to heat shock protein 90 (HSP90) inhibition.J. Biol. Chem. 2014; 289: 18914-18927Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Jonkers I. Lis J.T. Getting up to speed with transcription elongation by RNA polymerase II.Nat. Rev. Mol. Cell Biol. 2015; 16: 167-177Crossref PubMed Scopus (468) Google Scholar, 45Mason P.B. Lis J.T. Cooperative and competitive protein interactions at the hsp70 promoter.J. Biol. Chem. 1997; 272: 33227-33233Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 46Park J.M. Werner J. Kim J.M. Lis J.T. Kim Y.J. Mediator, not holoenzyme, is directly recruited to the heat shock promoter by HSF upon heat shock.Mol. Cell. 2001; 8: 9-19Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), including SGO2, which recruits the subunit mediator complex MED12, essential for the strong transcriptional induction of HSPs genes (47Takii R. Fujimoto M. Matsumoto M. Srivastava P. Katiyar A. Nakayama K.I. Nakai A. The pericentromeric protein shugoshin 2 cooperates with HSF1 in heat shock response and RNA Pol II recruitment.EMBO J. 2019; 38e102566Crossref PubMed Scopus (11) Google Scholar). SGO2 binding to hypophosphorylated RNAPII targets it to the promoter of HSP genes by forming a complex with HSF1. Transcription is then induced by other transcription factors like P-TEFb, recruitment of which are mediated by HSF1 (48Lis J.T. Mason P. Peng J. Price D.H. Werner J. P-TEFb kinase recruitment and function at heat shock loci.Genes Dev. 2000; 14: 792-803Crossref PubMed Google Scholar). P-TEFb is sufficient to induce the phosphorylation of the serine 2 in the C-terminal domain of RNAPII, which leads to transcription elongation (48Lis J.T. Mason P. Peng J. Price D.H. Werner J. P-TEFb kinase recruitment and function at heat shock loci.Genes Dev. 2000; 14: 792-803Crossref PubMed Google Scholar, 49Marshall N.F. Peng J. Xie Z. Price D.H. Control of RNA polymerase II elongation potential by a novel Carboxyl-terminal domain kinase∗.J. Biol. Chem. 1996; 271: 27176-27183Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). However, a strong transcriptional induction requires the nucleosomes positioned along the HSP70 gene body to be removed. The chromatin remodelers SWI/SNF in mammals and FACT together with the histone chaperone Spt6 in Drosophila melanogaster (D. melanogaster) are recruited by HSF1 to the HSP70 genes within minutes after heat shock to remove the nucleosomes (31Anckar J. Sistonen L. Regulation of HSF1 function in the heat stress response: Implications in aging and disease.Annu. Rev. Biochem. 2011; 80: 1089-1115Crossref PubMed Scopus (462) Google Scholar). Besides the activation of HSF1, heat shock induction of HSP70 in mammalian cells depends on the relocation of the HSP70 loci from the nuclear membrane to speckles (50Khanna N. Hu Y. Belmont A.S. HSP70 transgene directed motion to nuclear speckles facilitates heat shock activation.Curr. Biol. 2014; 24: 1138-1144Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 51Vera M. Singer R.H. Gene regulation: The HSP70 gene jumps when shocked.Curr. Biol. 2014; 24: R396-R398Abstract Full Text Full Text PDF PubMed Google Scholar). The rapid, active, and unidirectional movement of HSP70 loci is mediated by nuclear actin polymerization. The association of the HSP70 locus with speckles depends on the promoter sequence and determines the robust transcriptional activation of HSP70 upon heat shock stress. Although speckles contain serine 2–phosphorylated RNAPII and other components of the transcriptional machinery, the specific speckle factors critical for the transcriptional activation of HSP70 have not been yet identified. In yeast, genes encoding for different HSPs coalesce in discrete spots in the nucleus upon transcription stimulation. This interallelic clustering leads to the interaction between HSP104 and HSP12 loci and depends on the activation of their transcription. This result suggested the presence of specific transcriptional factories formed in response to heat stress, which could be coregulated by HSF1 (52Chowdhary S. Kainth A.S. Gross D.S. Heat shock protein genes undergo dynamic alteration in their three-dimensional structure and genome organization in response to thermal stress.Mol. Cell Biol. 2017; 37e00292-17Crossref PubMed Scopus (17) Google Scholar). The transcriptional induction of HSP genes during heat stress is accompanied by the upregulation of other non-HSP genes encoding for cytoskeleton and oxidative stress proteins and a massive downregulation of thousands of genes (For review: (53Vihervaara A. Duarte F.M. Lis J.T. Molecular mechanisms driving transcriptional stress responses.Nat. Rev. Genet. 2018; 19: 385-397Crossref PubMed Scopus (98) Google Scholar)). Detailed analysis of the position of the RNA polymerases, chromatin modifications, and domains in D. melanogaster and mammalian cells suggest that changes in the chromatin landscape cannot explain the rapid changes in transcriptional preferences upon heat shock (54Mueller B. Mieczkowski J. Kundu S. Wang P. Sadreyev R. Tolstorukov M.Y. Kingston R.E. Widespread changes in nucleosome accessibility without changes in nucleosome occupancy during a rapid transcriptional induction.Genes Dev. 2017; 31: 451-462Crossref PubMed Scopus (55) Google Scholar, 55Vihervaara A. Mahat D.B. Guertin M.J. Chu T. Danko C.G. Lis J.T. Sistonen L. Transcriptional response to stress is pre-wired by promoter and enhancer architecture.Nat. Commun. 2017; 8: 255Crossref PubMed Scopus (65) Google Scholar). Heat shock does not induce a global chromatin remodeling nor modifications of topology associated domains in human or D. melanogaster S2 cells (56Ray J. Munn P.R. Vihervaara A. Lewis J.J. Ozer A. Danko C.G. Lis J.T. Chromatin conformation remains stable upon extensive transcriptional cha
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