Heat Shock Transcription Factor Hsf1 Research Articles

The CBP-1/p300 Lysine Acetyltransferase Regulates the Heat Shock Response in C. elegans.

The decline of proteostasis is a hallmark of aging that is, in part, affected by the dysregulation of the heat shock response (HSR), a highly conserved cellular response to proteotoxic stress in the cell. The heat shock transcription factor HSF-1 is well-studied as a key regulator of proteostasis, but mechanisms that could be used to modulate HSF-1 function to enhance proteostasis during aging are largely unknown. In this study, we examined lysine acetyltransferase regulation of the HSR and HSF-1 in C. elegans. We performed an RNA interference screen of lysine acetyltransferases and examined mRNA expression of the heat-shock inducible gene hsp-16.2, a widely used marker for HSR activation. From this screen, we identified one acetyltransferase, CBP-1, the C. elegans homolog of mammalian CREB-binding protein CBP/p300, as a negative regulator of the HSR. We found that while knockdown of CBP-1 decreases the overall lifespan of the worm, it also enhances heat shock protein production upon heat shock and increases thermotolerance of the worm in an HSF-1 dependent manner. Similarly, we examined a hallmark of HSF-1 activation, the formation of nuclear stress bodies (nSBs). In analyzing the recovery rate of nSBs, we found that knockdown of CBP-1 enhanced the recovery and resolution of nSBs after stress. Collectively, our studies demonstrate a role of CBP-1 as a negative regulator of HSF-1 activity and its physiological effects at the organismal level upon stress.

Heat shock transcription factor HSF2 modulates the autophagy response through the BTG2-SOD2 axis

The heat shock transcription factor HSF1 regulates the inducible Hsp gene transcription, whereas HSF2 is involved in the constitutive transcription. HSFs can work for the non-heat shock genes transcription in a case-specific manner to facilitate normal cellular functions. Here, we demonstrate that HSF2 acts as an upstream regulator of heat shock-induced autophagy response in a rat histiocytoma. The heat-induced HSF2 transactivates the B-cell translocation gene-2 (BTG2) transcription, and the latter acts as a transcriptional coactivator for superoxide dismutase (SOD2). The altered HSF2 promoter occupancy on the BTG2 promoter enhances BTG2 transcription. Since SOD2 regulation is linked to mitochondrial redox sensing, HSF2 appears to act as a redox sensor in deciding the cell fate. The HSF2 shRNA or NFE2L2/BTG2 siRNA treatments have interfered with the autophagy response. We demonstrate that HSF2 is an upstream activator of autophagy response, and the HSF2-BTG2-SOD2 axis acts as a switch between the non-selective (micro/macro) and selective (chaperone-mediated) autophagy.

Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway

Maternal stress can have long-lasting epigenetic effects on offspring. To examine how epigenetic changes are triggered by stress, we examined the effects of activating the universal stress-responsive heat shock transcription factor HSF-1 in the germline of Caenorhabditis elegans. We show that, when activated in germ cells, HSF-1 recruits MET-2, the putative histone 3 lysine 9 (H3K9) methyltransferase responsible for repressive H3K9me2 (H3K9 dimethyl) marks in chromatin, and negatively bookmarks the insulin receptor daf-2 and other HSF-1 target genes. Increased H3K9me2 at these genes persists in adult progeny and shifts their stress response strategy away from inducible chaperone expression as a mechanism to survive stress and instead rely on decreased insulin/insulin growth factor (IGF-1)-like signaling (IIS). Depending on the duration of maternal heat stress exposure, this epigenetic memory is inherited by the next generation. Thus, paradoxically, HSF-1 recruits the germline machinery normally responsible for erasing transcriptional memory but, instead, establishes a heritable epigenetic memory of prior stress exposure.

Anticipatory Stress Responses and Immune Evasion in Fungal Pathogens.

In certain niches, microbes encounter environmental challenges that are temporally linked. In such cases, microbial fitness is enhanced by the evolution of anticipatory responses where the initial challenge simultaneously activates pre-emptive protection against the second impending challenge. The accumulation of anticipatory responses in domesticated yeasts, which have been termed 'adaptive prediction', has led to the emergence of 'core stress responses' that provide stress cross-protection. Protective anticipatory responses also seem to be common in fungal pathogens of humans. These responses reflect the selective pressures that these fungi have faced relatively recently in their evolutionary history. Consequently, some pathogens have evolved 'core environmental responses' which exploit host signals to trigger immune evasion strategies that protect them against imminent immune attack.

Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70-mediated trimer unzipping and dissociation from DNA.

The heat shock response is a universal transcriptional response to proteotoxic stress orchestrated by heat shock transcription factor Hsf1 in all eukaryotic cells. Despite over 40 years of intense research, the mechanism of Hsf1 activity regulation remains poorly understood at the molecular level. In metazoa, Hsf1 trimerizes upon heat shock through a leucine‐zipper domain and binds to DNA. How Hsf1 is dislodged from DNA and monomerized remained enigmatic. Here, using purified proteins, we demonstrate that unmodified trimeric Hsf1 is dissociated from DNA in vitro by Hsc70 and DnaJB1. Hsc70 binds to multiple sites in Hsf1 with different affinities. Hsf1 trimers are monomerized by successive cycles of entropic pulling, unzipping the triple leucine‐zipper. Starting this unzipping at several protomers of the Hsf1 trimer results in faster monomerization. This process directly monitors the concentration of Hsc70 and DnaJB1. During heat shock adaptation, Hsc70 first binds to a high‐affinity site in the transactivation domain, leading to partial attenuation of the response, and subsequently, at higher concentrations, Hsc70 removes Hsf1 from DNA to restore the resting state.

Endogenous siRNAs promote proteostasis and longevity in germline-less Caenorhabditis elegans.

How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in Caenorhabditis elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.

Identification of the nucleotide exchange factor BmGrpE and its role under high-temperature stress in silkworm, Bombyx mori.

The high-temperature stress gene GrpE plays an important role in coping with high-temperature stress. The mutation of key sites of this gene can improve the high-temperature resistance of organisms. In the present study, using complementary DNAs from the silkworm fat body as the template, the open reading frame sequence of the GrpE gene (BmGrpE) was amplified and was found to be 644 bp in length and encode a protein with a predicted molecular weight of 24.1 kDa. The presence of a binding site for the heat shock transcription factor (Hsf1) at -1440 bp upstream of its coding region indicates that BmGrpE may respond to high-temperature stress. BmGrpE was constitutively expressed throughout developmental stages, with the highest level observed in the 5th instar larvae stage. Moreover, in 5th instar larvae (the 3th day), BmGrpE was expressed in all tissues examined, with the highest levels in the fat body, silk gland, and midgut. Interestingly, under high-temperature stress, TiO2 nanoparticle treatment increased the messenger RNA levels of BmGrpE in the fat body and silk gland. After treatment with dsRNA of BmGrpE, the cell viability of BmN cells was significantly decreased under 34°C and H2 O2 stress (p < .05). Mutation of BmGrpE (H163L) enhanced the resistance of BmN cells under high-temperature stress. These results provide new clues for the study of molecular mechanisms of insect resistance to high temperatures.

The heat shock transcription factor HSF-1 protects Caenorhabditis elegans from peroxide stress

Cells induce conserved defense mechanisms that protect them from oxidative stress. How these defenses are regulated in multicellular organisms is incompletely understood. Here, we show that the heat shock transcription factor HSF-1 protects the nematode Caenorhabditis elegans from the oxidative stress caused by environmental peroxide. In response to a heat shock or a mild temperature increase, HSF-1 protects the nematodes from subsequent peroxide stress in a manner that depends on HSF-1’s transactivation domain. At constant temperature, HSF-1 protects the nematodes from peroxide stress independently of its transactivation domain, likely by inducing the expression of asp-4/cathepsin and dapk-1/dapk. Thus, two distinct HSF-1-dependent processes protect C. elegans from peroxide stress.

Effects of chlorogenic acid on thermal stress tolerance in C. elegans via HIF-1, HSF-1 and autophagy

BackgroundChlorogenic acid (CGA) is a polyphenol widely distributed in plants and plant-derived food with antioxidant and protective activities against cell stress. Caenorhabditis elegans is a model organism particularly useful for understanding the molecular and biochemical mechanisms associated with aging and stress in mammals. In C. elegans, CGA was shown to improve resistance to thermal, while the underlying mechanisms that lead to this effect require further understanding. PurposeThe present study was conducted to investigate the underlying molecular mechanisms behind CGA response conferring thermotolerance to C. elegans. Methods and resultsSignaling pathways that could be involved in the CGA-induced thermotolerance were evaluated in C. elegans strains with loss-of-function mutation. CGA-induced thermotolerance required hypoxia-inducible factor HIF-1 but no insulin pathway. CGA exposition (1.4 µM CGA for 18 h) before thermal stress treatment increased HIF-1 levels and activity. HIF-1 activation could be partly attributed to an increase in radical oxygen species and a decrease in superoxide dismutase activity. In addition, CGA exposition before thermal stress also increased autophagy just as hormetic heat condition (HHC), worms incubated at 36 °C for 1 h. RNAi experiments evidenced that autophagy was increased by CGA via HIF-1, heat-shock transcription factor HSF-1 and heat-shock protein HSP-16 and HSP-70. In contrast, autophagy induced by HHC only required HSF-1 and HSP-70. Moreover, suppression of autophagy induction showed the significance of this process for adapting C. elegans to cope with thermal stress. ConclusionThis study demonstrates that CGA-induced thermotolerance in C. elegans is mediated by HIF-1 and downstream, by HSF-1, HSPs and autophagy resembling HHC.

NOTCH1 Signaling Hijacks the Stress Response to Promote T-ALL

Abstract The heat shock transcription factor HSF1 is upregulated in patients with T-ALL.

Data-driven dynamical model indicates that the heat shock response in Chlamydomonas reinhardtii is tailored to handle natural temperature variation.

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of unfolded proteins initiates the synthesis of heat shock proteins through the heat shock transcription factor HSF1. While the molecular mechanisms are qualitatively well characterized, our quantitative understanding of the underlying dynamics is still very limited. Here, we study the dynamics of HSR in the photosynthetic model organism Chlamydomonas reinhardtii with a data-driven mathematical model of HSR. We based our dynamical model mostly on mass action kinetics, with a few nonlinear terms. The model was parametrized and validated by several independent datasets obtained from the literature. We demonstrate that HSR quantitatively and significantly differs if an increase in temperature of the same magnitude occurs abruptly, as often applied under laboratory conditions, or gradually, which would rather be expected under natural conditions. In contrast to rapid temperature increases, under gradual changes only negligible amounts of misfolded proteins accumulate, indicating that the HSR of C. reinhardtii efficiently avoids the accumulation of misfolded proteins under conditions most likely to prevail in nature. The mathematical model we developed is a flexible tool to simulate the HSR to different conditions and complements the current experimental approaches.

Regulation of the heat shock transcription factor Hsf1 in fungi: implications for temperature-dependent virulence traits.

The impact of fungal pathogens on human health is devastating. For fungi and other pathogens, a key determinant of virulence is the capacity to thrive at host temperatures, with elevated temperature in the form of fever as a ubiquitous host response to defend against infection. A prominent feature of cells experiencing heat stress is the increased expression of heat shock proteins (Hsps) that play pivotal roles in the refolding of misfolded proteins in order to restore cellular homeostasis. Transcriptional activation of this heat shock response is orchestrated by the essential heat shock transcription factor, Hsf1. Although the influence of Hsf1 on cellular stress responses has been studied for decades, many aspects of its regulation and function remain largely enigmatic. In this review, we highlight our current understanding of how Hsf1 is regulated and activated in the model yeast Saccharomyces cerevisiae, and highlight exciting recent discoveries related to its diverse functions under both basal and stress conditions. Given that thermal adaption is a fundamental requirement for growth and virulence in fungal pathogens, we also compare and contrast Hsf1 activation and function in other fungal species with an emphasis on its role as a critical regulator of virulence traits.

Regulation of Functional Proteome by the Heat Shock Response and Proteostasis Network

Cellular health and proteome function is maintained by the proteostasis network (PN) comprised of molecular chaperones, transport pathways, the ubiquitin‐dependent proteasome, and autophagy clearance mechanisms. The dynamic properties of the PN are regulated by cell stress responses including the heat shock response (HSR) and the unfolded protein responses of the endoplasmic reticulum (UPRER) and mitochondria (UPRMITO). To understand the biology of organismal proteostasis, we have examined the properties of the PN in different tissues throughout the lifespan of C. elegans. The transition from development through reproduction into adulthood and aging places a tremendous demand on quality control processes and protein biogenesis. In early development, heat shock transcription factor HSF‐1 is essential, and target gene expression is co‐regulated with the cell cycle factor, E2F, to control a small subset of chaperone and PN genes involved in rapid anabolic growth. HSF‐1 is also involved in suppression of protein degradation pathways in early development. At reproductive maturity, the HSR is inhibited in somatic tissues by signals from the germ line stem cells that place repressive H3K27me3 chromatin marks at HS gene loci, repressing HSF‐1 DNA binding and transcription of chaperone genes, leading to the collapse of proteostasis in aging. These inhibitory signals on organismal proteostasis can be reversed genetically by overexpression of the jumonji demethylase, inhibition of germ line signaling, or induction of mitochondrial stress, either by mild downregulation of components of the electron transport chain, xenobiotics, and certain pathogenic bacteria to prevent the proteostasis collapse that occurs in early adult aging. These observations reveal that the regulation of molecular chaperones and other components of the PN by cell stress response pathways in aging is the basis for increased risk for misfolding and aggregation as occurs in neurodegenerative diseases and other protein conformational diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Transient Intracellular Acidification Regulates the Core Transcriptional Heat Shock Response

Cellular stress induces rapid expression of genes encoding molecular chaperones. Stress also triggers transient intracellular acidification which, by unknown mechanisms, is broadly associated with increased stress resistance in eukaryotes. Here, using budding yeast as a model, we discover that preventing cells from transiently acidifying during heat shock compromises induction of molecular chaperones and fitness. Both acidification and subsequent restoration of intracellular pH are required for robust chaperone induction, with pH recovery and chaperone production predicting resumption of division in single cells. Failure to acidify specifically suppresses genes regulated by the conserved heat shock transcription factor Hsf1, which is repressed by chaperones under non-stress conditions. The failure of heat to induce the heat shock response without concomitant acidification implicates pH-sensitive stress-sensing proteins in recruiting chaperone repressors to activate Hsf1 under physiological conditions. Our findings reveal a central, causal role for intracellular pH in the eukaryotic transcriptional stress response.

북방전복 (Haliotis discus hannai) 에서 분리한 열충격인자 1 (HSF1) 유전자 동정 및 발현에 대한 연구

북방전복 (Haliotis discus hannai) 에서 분리한 열충격인자 1 (HSF1) 유전자 동정 및 발현에 대한 연구

Correction for Gabai et al., “Heat Shock Transcription Factor Hsf1 Is Involved in Tumor Progression via Regulation of Hypoxia-Inducible Factor 1 and RNA-Binding Protein HuR”

Volume 32, no. 5, p. 929–940, 2012, [https://doi.org/10.1128/MCB.05921-11][1]. Page 938, Fig. 6A: During preparation of the manuscript, the left actin panel was accidentally replicated in the right actin panel. This error does not affect any conclusions of the study. We apologize for the error

Ethanol Stimulates Locomotion via a Gαs-Signaling Pathway in IL2 Neurons in Caenorhabditis elegans.

Alcohol is a potent pharmacological agent when consumed acutely at sufficient quantities and repeated overuse can lead to addiction and deleterious effects on health. Alcohol is thought to modulate neuronal function through low-affinity interactions with proteins, in particular with membrane channels and receptors. Paradoxically, alcohol acts as both a stimulant and a sedative. The exact molecular mechanisms for the acute effects of ethanol on neurons, as either a stimulant or a sedative, however remain unclear. We investigated the role that the heat shock transcription factor HSF-1 played in determining a stimulatory phenotype of Caenorhabditis elegans in response to physiologically relevant concentrations of ethanol (17 mM; 0.1% v/v). Using genetic techniques, we demonstrate that either RNA interference of hsf-1 or use of an hsf-1(sy441) mutant lacked the enhancement of locomotion in response to acute ethanol exposure evident in wild-type animals. We identify that the requirement for HSF-1 in this phenotype was IL2 neuron-specific and required the downstream expression of the α-crystallin ortholog HSP-16.48 Using a combination of pharmacology, optogenetics, and phenotypic analyses we determine that ethanol activates a Gαs-cAMP-protein kinase A signaling pathway in IL2 neurons to stimulate nematode locomotion. We further implicate the phosphorylation of a specific serine residue (Ser322) on the synaptic protein UNC-18 as an end point for the Gαs-dependent signaling pathway. These findings establish and characterize a distinct neurosensory cell signaling pathway that determines the stimulatory action of ethanol and identifies HSP-16.48 and HSF-1 as novel regulators of this pathway.

HSF-1 is a regulator of miRNA expression in Caenorhabditis elegans.

The ability of an organism to sense and adapt to environmental stressors is essential for proteome maintenance and survival. The highly conserved heat shock response is a survival mechanism employed by all organisms, including the nematode Caenorhabditis elegans, upon exposure to environmental extremes. Transcriptional control of the metazoan heat shock response is mediated by the heat shock transcription factor HSF-1. In addition to regulating global stress-responsive genes to promote stress-resistance and survival, HSF-1 has recently been shown to regulate stress-independent functions in controlling development, metabolism, and longevity. However, the indirect role of HSF-1 in coordinating stress-dependent and -independent processes through post-transcriptional regulation is largely unknown. MicroRNAs (miRNAs) have emerged as a class of post-transcriptional regulators that control gene expression through translational repression or mRNA degradation. To determine the role of HSF-1 in regulating miRNA expression, we have performed high-throughput small RNA-sequencing in C. elegans grown in the presence and absence of hsf-1 RNAi followed by treatment with or without heat shock. This has allowed us to uncover the miRNAs regulated by HSF-1 via heat-dependent and -independent mechanisms. Integrated miRNA/mRNA target-prediction analyses suggest HSF-1 as a post-transcriptional regulator of development, metabolism, and longevity through regulating miRNA expression. This provides new insight into the possible mechanism by which HSF-1 controls these processes. We have also uncovered oxidative stress response factors and insulin-like signaling factors as a common link between processes affected by HSF-1-regulated miRNAs in stress-dependent and -independent mechanisms, respectively. This may provide a role for miRNAs in regulating cross-talk between various stress responses. Our work therefore uncovers an interesting potential role for HSF-1 in post-transcriptionally controlling gene expression in C. elegans, and suggests a mechanism for cross-talk between stress responses.

Coffee extract and caffeine enhance the heat shock response and promote proteostasis in an HSF-1-dependent manner in Caenorhabditis elegans.

As the population ages, there is a critical need to uncover strategies to combat diseases of aging. Studies in the soil-dwelling nematode Caenorhabditis elegans have demonstrated the protective effects of coffee extract and caffeine in promoting the induction of conserved longevity pathways including the insulin-like signaling pathway and the oxidative stress response. We were interested in determining the effects of coffee and caffeine treatment on the regulation of the heat shock response. The heat shock response is a highly conserved cellular response that functions as a cytoprotective mechanism during stress, mediated by the heat shock transcription factor HSF-1. In the worm, HSF-1 not only promotes protection against stress but is also essential for development and longevity. Induction of the heat shock response has been suggested to be beneficial for diseases of protein conformation by preventing protein misfolding and aggregation, and as such has been proposed as a therapeutic target for age-associated neurodegenerative disorders. In this study, we demonstrate that coffee is a potent, dose-dependent, inducer of the heat shock response. Treatment with a moderate dose of pure caffeine was also able to induce the heat shock response, indicating caffeine as an important component within coffee for producing this response. The effects that we observe with both coffee and pure caffeine on the heat shock response are both dependent on HSF-1. In a C. elegans Huntington's disease model, worms treated with caffeine were protected from polyglutamine aggregates and toxicity, an effect that was also HSF-1-dependent. In conclusion, these results demonstrate caffeinated coffee, and pure caffeine, as protective substances that promote proteostasis through induction of the heat shock response.

The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans.

BackgroundThe heat shock response, induced by cytoplasmic proteotoxic stress, is one of the most highly conserved transcriptional responses. This response, driven by the heat shock transcription factor HSF1, restores proteostasis through the induction of molecular chaperones and other genes. In addition to stress-dependent functions, HSF1 has also been implicated in various stress-independent functions. In C. elegans, the HSF1 homolog HSF-1 is an essential protein that is required to mount a stress-dependent response, as well as to coordinate various stress-independent processes including development, metabolism, and the regulation of lifespan. In this work, we have performed RNA-sequencing for C. elegans cultured in the presence and absence of hsf-1 RNAi followed by treatment with or without heat shock. This experimental design thus allows for the determination of both heat shock-dependent and -independent biological targets of HSF-1 on a genome-wide level.ResultsOur results confirm that C. elegans HSF-1 can regulate gene expression in both a stress-dependent and -independent fashion. Almost all genes regulated by HS require HSF-1, reinforcing the central role of this transcription factor in the response to heat stress. As expected, major categories of HSF-1-regulated genes include cytoprotection, development, metabolism, and aging. Within both the heat stress-dependent and -independent gene groups, significant numbers of genes are upregulated as well as downregulated, demonstrating that HSF-1 can both activate and repress gene expression either directly or indirectly. Surprisingly, the cellular process most highly regulated by HSF-1, both with and without heat stress, is cuticle structure. Via network analyses, we identify a nuclear hormone receptor as a common link between genes that are regulated by HSF-1 in a HS-dependent manner, and an epidermal growth factor receptor as a common link between genes that are regulated by HSF-1 in a HS-independent manner. HSF-1 therefore coordinates various physiological processes in C. elegans, and HSF-1 activity may be coordinated across tissues by nuclear hormone receptor and epidermal growth factor receptor signaling.ConclusionThis work provides genome-wide HSF-1 regulatory networks in C. elegans that are both heat stress-dependent and -independent. We show that HSF-1 is responsible for regulating many genes outside of classical heat stress-responsive genes, including genes involved in development, metabolism, and aging. The findings that a nuclear hormone receptor may coordinate the HS-induced HSF-1 transcriptional response, while an epidermal growth factor receptor may coordinate the HS-independent response, indicate that these factors could promote cell non-autonomous signaling that occurs through HSF-1. Finally, this work highlights the genes involved in cuticle structure as important HSF-1 targets that may play roles in promoting both cytoprotection as well as longevity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2837-5) contains supplementary material, which is available to authorized users.