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1.
Front Biosci (Landmark Ed) ; 29(2): 53, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38420805

RESUMO

BACKGROUND: Recently, miRNAs are demonstrated to restrain mRNA translation through novel pattern with bind complementary sites in the coding sequence (CDS). Heat Shock Transcription Factor 4 (HSF4) has been newly described as a tumor-associated transcription factor. Therefore, the present study intends to explore miRNAs that bind CDS region of HSF4, and identify the function of their interactions in the malignant biological behavior of colorectal cancer (CRC). METHODS: Prognostic value of HSF4 and correlation between HSF4 and MACC1 expression were estimated via bioinformatics with the Cancer Genome Atlas (TCGA) data. HSF4 and downstream MACC1/STAT3 signaling cascade was characterized by immunoblotting. To characterize the effects of miR-330-5p and HSF4 on the malignant phenotype of CRC cells by functional experiments. The binding activity of miR-330-5p to coding sequence (CDS) of HSF4 was identified using DIANA-microT-CDS algorithm and dual-luciferase reporter assay. RESULTS: HSF4 was aberrantly overexpressed and associated with poor outcomes of CRC patients. Overexpression of HSF4 was correlated with Tumor Node Metastasis stage, and positively regulated malignant behaviors such as growth, migration, invasion of CRC cells. Moreover, miR-330-5p suppressed CRC cell growth, colony formation, migration and invasive. Interestingly, miR-330-5p recognized complementary sites within the HSF4 CDS region to reduce HSF4 expression. In rescue experiments, restoration of HSF4 expression functionally alleviated miR-330-5p-induced inhibition of cell growth, colon formation, invasion, and wound healing of CRC cells. HSF4 was associated positively with the well-known oncogenic factor MACC1 in TCGA cohort CRC samples, and knockdown of HSF4 resulted in downregulation of MACC1. In mechanism, MACC1 was suppressed upon miR-330-5p-induced downregulation of HSF4, leading to inactivation of phosphorylation of downstream STAT3. CONCLUSION: miR-330-5p suppresses tumors by directly inhibiting HSF4 to negatively modify activity of MACC1/STAT3 pathway.


Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , Neoplasias Colorretais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proliferação de Células/genética , Transdução de Sinais/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transativadores/genética
2.
Sci Rep ; 14(1): 3158, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326350

RESUMO

Magnolol is a naturally occurring polyphenolic compound in many edible plants, which has various biological effects including anti-aging and alleviating neurodegenerative diseases. However, the underlying mechanism on longevity is uncertain. In this study, we investigated the effect of magnolol on the lifespan of Caenorhabditis elegans and explored the mechanism. The results showed that magnolol treatment significantly extended the  lifespan of nematode and alleviated senescence-related decline in the nematode model. Meanwhile, magnolol enhanced stress resistance to heat shock, hydrogen peroxide (H2O2), mercuric potassium chloride (MeHgCl) and paraquat (PQ) in nematode. In addition, magnolol reduced reactive oxygen species and malondialdehyde (MDA) levels, and increased superoxide dismutase and catalase (CAT) activities in nematodes. Magnolol also up-regulated gene expression of sod-3, hsp16.2, ctl-3, daf-16, skn-1, hsf-1, sir2.1, etc., down-regulated gene expression of daf-2, and promoted intranuclear translocation of daf-16 in nematodes. The lifespan-extending effect of magnolol were reversed in insulin/IGF signaling (IIS) pathway-related mutant lines, including daf-2, age-1, daf-16, skn-1, hsf-1 and sir-2.1, suggesting that IIS signaling is involved in the modulation of longevity by magnolol. Furthermore, magnolol improved the age-related neurodegeneration in PD and AD C. elegans models. These results indicate that magnolol may enhance lifespan and health span through IIS and sir-2.1 pathways. Thus, the current findings implicate magnolol as a potential candidate to ameliorate the symptoms of aging.


Assuntos
Compostos de Bifenilo , Proteínas de Caenorhabditis elegans , Lignanas , Longevidade , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Peróxido de Hidrogênio/metabolismo , Antioxidantes/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Insulina/metabolismo , Estresse Oxidativo , Fatores de Transcrição Forkhead/metabolismo
3.
Molecules ; 29(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38398658

RESUMO

Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aß-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway.


Assuntos
Proteínas de Caenorhabditis elegans , Dendrobium , Animais , Longevidade , Caenorhabditis elegans , Dendrobium/metabolismo , Estresse Oxidativo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Etanol/metabolismo , Fatores de Transcrição Forkhead/metabolismo
4.
Gene ; 893: 147945, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38381511

RESUMO

To investigate the regulatory role of heat shock transcription factor 1 of sea slug Onchidium reevesii (OrHSF1) on Hsp70 expression in the sea slug under stress , the OrHSF1 gene was cloned and bioinformatics analysis was performed, then the gene and protein expressions by RNA interference (RNAi) mediated knockdown of OrHSF1 expression were measured to clarify the regulatory relationship between OrHSF1 and Hsp70 under low-frequency noise (LFN) stress. Our study was the first to clone a 1572 bp sequence of the OrHSF1 gene, with the sequence coding for amino acids (CDS) being 729 bp, encoding 243 amino acids. O. reevesii shared a close evolutionary relationship with mollusks such as the Aplysia californica. OrHSF1 gene is widely expressed in different tissues of sea slugs, with the highest expression in the intestine and the lowest in the reproductive glands. Furthermore, we used RNA interference (RNAi) as a tool to silence the OrHSF1 gene in the central nervous system (CNS) and the results indicated that gene silencing was occurring systematically in the CNS and the suppression of OrHSF1 expression by RNAi-mediated gene silencing altered the expression of Hsp70; besides, the expression trends of OrHSF1 gene and Hsp70 were consistent in the 3 and 5-day RNAi experiment. Moreover, in sea slugs injected with siHSF1 and exposed to LFN, the mRNA expression and protein expression of Hsp70 in the CNS were significantly decreased compared to the low-frequency noise group (P < 0.05). This study demonstrated that OrHSF1 regulates Hsp70 expression in marine mollusks under low-frequency noise, and HSF1-Hsp70 axis plays a key role in stress response.


Assuntos
Aplysia , Gastrópodes , Animais , Fatores de Transcrição de Choque Térmico/genética , Gastrópodes/genética , Aminoácidos , Proteínas de Choque Térmico HSP70/genética , Clonagem Molecular
5.
Autophagy ; 20(3): 659-674, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38290972

RESUMO

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.


Assuntos
Anexina A2 , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Autofagia/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fatores de Transcrição de Choque Térmico/genética , Anexina A2/genética , Linhagem Celular Tumoral , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Doxorrubicina , Sirolimo
6.
EMBO J ; 43(3): 437-461, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38228917

RESUMO

Plants are often exposed to recurring adverse environmental conditions in the wild. Acclimation to high temperatures entails transcriptional responses, which prime plants to better withstand subsequent stress events. Heat stress (HS)-induced transcriptional memory results in more efficient re-induction of transcription upon recurrence of heat stress. Here, we identified CDK8 and MED12, two subunits of the kinase module of the transcription co-regulator complex, Mediator, as promoters of heat stress memory and associated histone modifications in Arabidopsis. CDK8 is recruited to heat-stress memory genes by HEAT SHOCK TRANSCRIPTION FACTOR A2 (HSFA2). Like HSFA2, CDK8 is largely dispensable for the initial gene induction upon HS, and its function in transcriptional memory is thus independent of primary gene activation. In addition to the promoter and transcriptional start region of target genes, CDK8 also binds their 3'-region, where it may promote elongation, termination, or rapid re-initiation of RNA polymerase II (Pol II) complexes during transcriptional memory bursts. Our work presents a complex role for the Mediator kinase module during transcriptional memory in multicellular eukaryotes, through interactions with transcription factors, chromatin modifications, and promotion of Pol II efficiency.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Resposta ao Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Ativação Transcricional , Nucleotidiltransferases/metabolismo , Complexo Mediador/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Quinase 8 Dependente de Ciclina/genética , Quinase 8 Dependente de Ciclina/metabolismo
7.
Cancer Immunol Immunother ; 73(2): 25, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38280079

RESUMO

Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism.


Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Resistência a Medicamentos , Etoposídeo/farmacologia , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico , Fatores de Transcrição/metabolismo , Macrófagos Associados a Tumor/metabolismo
8.
Cell Stress Chaperones ; 29(1): 116-142, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38244765

RESUMO

The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions. This process hinges on the upregulation of heat shock proteins (HSPs) and other chaperones, notably the 70 kDa family of heat shock proteins, under the command of the heat shock transcription factor-1. However, in the context of chronic degenerative disorders characterized by persistent low-grade inflammation (such as insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases) a gradual suppression of the HSR does occur. This work delves into the mechanisms behind this phenomenon. It explores how the Western diet and sedentary lifestyle, culminating in the endoplasmic reticulum stress within adipose tissue cells, trigger a cascade of events. This cascade includes the unfolded protein response and activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome, leading to the emergence of the senescence-associated secretory phenotype and the propagation of inflammation throughout the body. Notably, the activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome not only fuels inflammation but also sabotages the HSR by degrading human antigen R, a crucial mRNA-binding protein responsible for maintaining heat shock transcription factor-1 mRNA expression and stability on heat shock gene promoters. This paper underscores the imperative need to comprehend how chronic inflammation stifles the HSR and the clinical significance of evaluating the HSR using cost-effective and accessible tools. Such understanding is pivotal in the development of innovative strategies aimed at the prevention and treatment of these chronic inflammatory ailments, which continue to take a heavy toll on global health and well-being.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Fatores de Transcrição de Choque Térmico , Inflamassomos/metabolismo , Inflamassomos/farmacologia , Resposta ao Choque Térmico , Proteínas de Choque Térmico/metabolismo , Inflamação , RNA Mensageiro , Proteínas NLR/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo
9.
Int J Mol Sci ; 25(2)2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38256051

RESUMO

Drought stress can seriously affect the yield and quality of wheat (Triticum aestivum). So far, although few wheat heat shock transcription factors (Hsfs) have been found to be involved in the stress response, the biological functions of them, especially the members of the HsfC (heat shock transcription factor C) subclass, remain largely unknown. Here, we identified a class C encoding gene, TaHsfC3-4, based on our previous omics data and analyzed its biological function in transgenic plants. TaHsfC3-4 encodes a protein containing 274 amino acids and shows the basic characteristics of the HsfC class. Gene expression profiles revealed that TaHsfC3-4 was constitutively expressed in many tissues of wheat and was induced during seed maturation. TaHsfC3-4 could be upregulated by PEG and abscisic acid (ABA), suggesting that this Hsf may be involved in the regulation pathway depending on ABA in drought resistance. Further results represented that TaHsfC3-4 was localized in the nucleus but had no transcriptional activation activity. Notably, overexpression of TaHsfC3-4 in Arabidopsis thaliana pyr1pyl1pyl2pyl4 (pyr1pyl124) quadruple mutant plants complemented the ABA-hyposensitive phenotypes of the quadruple mutant including cotyledon greening, root elongation, seedling growth, and increased tolerance to drought, indicating positive roles of TaHsfC3-4 in the ABA signaling pathway and drought tolerance. Furthermore, we identified TaHsfA2-11 as a TaHsfC3-4-interacting protein by yeast two-hybrid (Y2H) screening. The experimental data show that TaHsfC3-4 can indeed interact with TaHsfA2-11 in vitro and in vivo. Moreover, transgenic Arabidopsis TaHsfA2-11 overexpression lines exhibited enhanced drought tolerance, too. In summary, our study confirmed the role of TaHsfC3-4 in response to drought stress and provided a target locus for marker-assisted selection breeding to improve drought tolerance in wheat.


Assuntos
Arabidopsis , Resistência à Seca , Regulação para Cima , Triticum/genética , Fatores de Transcrição de Choque Térmico , Ácido Abscísico/farmacologia , Arabidopsis/genética , Interleucina-6
10.
Biogerontology ; 25(1): 147-160, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37707683

RESUMO

Brain aging is a major risk factor for cognitive diseases such as Alzheimer's disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.


Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição , Camundongos , Animais , Proteínas de Ligação a DNA/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Fatores de Transcrição/genética , Envelhecimento/metabolismo , Encéfalo/metabolismo
11.
Cancer Res ; 84(2): 276-290, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-37890164

RESUMO

Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. To provide a better understanding of the biological processes regulated by HSF1, here we developed an HSF1 activity signature (HAS) and found that it was negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased breast tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells rescued the reduction in growth of HSF1-deficient tumors, suggesting HSF1 prevents CD8+ T-cell influx to avoid immune-mediated tumor killing. HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T-cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer. SIGNIFICANCE: The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.


Assuntos
Neoplasias da Mama , Proteínas de Ligação a DNA , Humanos , Feminino , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Mama/patologia , Fatores de Transcrição de Choque Térmico/genética , Linhagem Celular Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo
12.
New Phytol ; 241(4): 1574-1591, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38062856

RESUMO

Fucoxanthin, a natural carotenoid that has substantial pharmaceutical value due to its anticancer, antioxidant, antiobesity, and antidiabetic properties, is biosynthesized from glyceraldehyde-3-phosphate (G3P) via a series of enzymatic reactions. However, our understanding of the transcriptional mechanisms involved in fucoxanthin biosynthesis remains limited. Using reverse genetics, the med8 mutant was identified based on its phenotype of reduced fucoxanthin content, and the biological functions of MED8 in fucoxanthin synthesis were characterized using approaches such as gene expression, protein subcellular localization, protein-protein interaction and chromatin immunoprecipitation assay. Gene-editing mutants of MED8 exhibited decreased fucoxanthin content as well as reduced expression levels of six key genes involved in fucoxanthin synthesis, namely DXS, PSY1, ZDS-like, CRTISO5, ZEP1, and ZEP3, when compared to the wild-type (WT) strain. Furthermore, we showed that MED8 interacts with HSF3, and genetic analysis revealed their shared involvement in the genetic pathway governing fucoxanthin synthesis. Additionally, HSF3 was required for MED8 association with the promoters of the six fucoxanthin synthesis genes. In conclusion, MED8 and HSF3 are involved in fucoxanthin synthesis by modulating the expression of the fucoxanthin synthesis genes. Our results increase the understanding of the molecular regulation mechanisms underlying fucoxanthin synthesis in the diatom P. tricornutum.


Assuntos
Diatomáceas , Fatores de Transcrição de Choque Térmico/metabolismo , Diatomáceas/genética , Diatomáceas/metabolismo , Xantofilas/metabolismo , Carotenoides/metabolismo
13.
Mucosal Immunol ; 17(1): 94-110, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37944754

RESUMO

The heat shock response is a critical component of the inflammatory cascade that prevents misfolding of new proteins and regulates immune responses. Activation of clusters of differentiation (CD)4+ T cells causes an upregulation of heat shock transcription factor, heat shock factor 1 (HSF1). We hypothesized that HSF1 promotes a pro-regulatory phenotype during inflammation. To validate this hypothesis, we interrogated cell-specific HSF1 knockout mice and HSF1 transgenic mice using in vitro and in vivo techniques. We determined that while HSF1 expression was induced by anti-CD3 stimulation alone, the combination of anti-CD3 and transforming growth factor ß, a vital cytokine for regulatory T cell (Treg) development, resulted in increased activating phosphorylation of HSF1, leading to increased nuclear translocation and binding to heat shock response elements. Using chromatin immunoprecipitation (ChIP), we demonstrate the direct binding of HSF1 to foxp3 in isolated murine CD4+ T cells, which in turn coincided with induction of FoxP3 expression. We defined that conditional knockout of HSF1 decreased development and function of Tregs and overexpression of HSF1 led to increased expression of FoxP3 along with enhanced Treg suppressive function. Adoptive transfer of CD45RBHigh CD4 colitogenic T cells along with HSF1 transgenic CD25+ Tregs prevented intestinal inflammation when wild-type Tregs did not. Finally, overexpression of HSF1 provided enhanced barrier function and protection from murine ileitis. This study demonstrates that HSF1 promotes Treg development and function and may represent both a crucial step in the development of induced regulatory T cells and an exciting target for the treatment of inflammatory diseases with a regulatory T-cell component. SIGNIFICANCE STATEMENT: The heat shock response (HSR) is a canonical stress response triggered by a multitude of stressors, including inflammation. Evidence supports the role of the HSR in regulating inflammation, yet there is a paucity of data on its influence in T cells specifically. Gut homeostasis reflects a balance between regulatory clusters of differentiation (CD)4+ T cells and pro-inflammatory T-helper (Th)17 cells. We show that upon activation within T cells, heat shock factor 1 (HSF1) translocates to the nucleus, and stimulates Treg-specific gene expression. HSF1 deficiency hinders Treg development and function and conversely, HSF1 overexpression enhances Treg development and function. While this work, focuses on HSF1 as a novel therapeutic target for intestinal inflammation, the findings have significance for a broad range of inflammatory conditions.


Assuntos
Inflamação , Linfócitos T Reguladores , Animais , Camundongos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico , Camundongos Knockout , Camundongos Transgênicos
14.
Mol Cell ; 84(1): 80-93, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38103561

RESUMO

Cellular homeostasis is constantly challenged by a myriad of extrinsic and intrinsic stressors. To mitigate the stress-induced damage, cells activate transient survival programs. The heat shock response (HSR) is an evolutionarily well-conserved survival program that is activated in response to proteotoxic stress. The HSR encompasses a dual regulation of transcription, characterized by rapid activation of genes encoding molecular chaperones and concomitant global attenuation of non-chaperone genes. Recent genome-wide approaches have delineated the molecular depth of stress-induced transcriptional reprogramming. The dramatic rewiring of gene and enhancer networks is driven by key transcription factors, including heat shock factors (HSFs), that together with chromatin-modifying enzymes remodel the 3D chromatin architecture, determining the selection of either gene activation or repression. Here, we highlight the current advancements of molecular mechanisms driving transcriptional reprogramming during acute heat stress. We also discuss the emerging implications of HSF-mediated stress signaling in the context of physiological and pathological conditions.


Assuntos
Proteostase , Fatores de Transcrição , Proteostase/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Resposta ao Choque Térmico/genética , Chaperonas Moleculares/genética , Cromatina/genética , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo
15.
Elife ; 122023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38059913

RESUMO

Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the 'rewiring stress response', and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.


Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição , Animais , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Mamíferos/metabolismo
16.
Mol Biol (Mosk) ; 57(6): 949-964, 2023.
Artigo em Russo | MEDLINE | ID: mdl-38062952

RESUMO

This review considers the recent progress on the role of heat shock proteins (HSPs), as well as transcription factors of heat shock proteins genes (HSFs) in protecting plants from oxidative stress induced by various types of abiotic and biotic stresses. HSPs are pleiotropic proteins involved in various intracellular processes and performing many important functions. In particular, HSPs increase plant resistance to stress by protecting the structure and activity of proteins of the antioxidant system. Overexpression of Hsp genes under stressful conditions, leading to an increased content of HSPs, can be used as a marker of oxidative stress. Plant HSFs are encoded by large gene families with variable sequences, expression and function. Plant HSFs regulate transcription of a wide range of stress-induced genes, including HSPs and other chaperones, reactive oxygen species scavengers, enzymes involved in protective metabolic reactions and osmolytic biosynthesis, or other transcriptional factors. Genome-wide analysis of Arabidopsis, rice, poplar, lettuce, and wheat revealed a complex network of interaction between the Hsps and Hsfs gene families that form plant protection against oxidative stress. Plant protection systems are discussed, with special emphasis on the role of HSPs and HSFs in plant responses to stress, which will be useful for the development of technologies to increase productivity and stress resistance of plant crops.


Assuntos
Proteínas de Choque Térmico , Fatores de Transcrição , Proteínas de Choque Térmico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Plantas/genética , Plantas/metabolismo , Estresse Oxidativo/genética , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Fatores de Transcrição de Choque Térmico/genética , Resposta ao Choque Térmico/genética
17.
Int J Mol Sci ; 24(21)2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37958622

RESUMO

Heat shock transcription factors (HSFs) play a crucial role in regulating plant growth and response to various abiotic stresses. In this study, we conducted a comprehensive analysis of the AeHSF gene family at genome-wide level in kiwifruit (Actinidia eriantha), focusing on their functions in the response to abiotic stresses. A total of 41 AeHSF genes were identified and categorized into three primary groups, namely, HSFA, HSFB, and HSFC. Further transcriptome analysis revealed that the expression of AeHSFA2b/2c and AeHSFB1c/1d/2c/3b was strongly induced by salt, which was confirmed by qRT-PCR assays. The overexpression of AeHSFA2b in Arabidopsis significantly improved the tolerance to salt stress by increasing AtRS5, AtGolS1 and AtGolS2 expression. Furthermore, yeast one-hybrid, dual-luciferase, and electrophoretic mobility shift assays demonstrated that AeHSFA2b could bind to the AeRFS4 promoter directly. Therefore, we speculated that AeHSFA2b may activate AeRFS4 expression by directly binding its promoter to enhance the kiwifruit's tolerance to salt stress. These results will provide a new insight into the evolutionary and functional mechanisms of AeHSF genes in kiwifruit.


Assuntos
Actinidia , Tolerância ao Sal , Tolerância ao Sal/genética , Actinidia/genética , Actinidia/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Estresse Fisiológico/genética , Regiões Promotoras Genéticas , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Filogenia
18.
Int J Mol Sci ; 24(22)2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-38003725

RESUMO

With global warming, high temperatures have become a major environmental stress that inhibits plant growth and development. Plants evolve several mechanisms to cope with heat stress accordingly. One of the important mechanisms is the Hsf (heat shock factor)-Hsp (heat shock protein) signaling pathway. Therefore, the plant transcription factor Hsf family plays important roles in response to heat stress. All Hsfs can be divided into three classes (A, B, and C). Usually, class-A Hsfs are transcriptional activators, while class-B Hsfs are transcriptional repressors. In potato, our previous work identified 27 Hsfs in the genome and analyzed HsfA3 and HsfA4C functions that promote potato heat resistance. However, the function of HsfB is still elusive. In this study, the unique B5 member StHsfB5 in potato was obtained, and its characterizations and functions were comprehensively analyzed. A quantitative real-time PCR (qRT-PCR) assay showed that StHsfB5 was highly expressed in root, and its expression was induced by heat treatment and different kinds of phytohormones. The subcellular localization of StHsfB5 was in the nucleus, which is consistent with the characterization of transcription factors. The transgenic lines overexpressing StHsfB5 showed higher heat resistance compared with that of the control nontransgenic lines and inhibitory lines. Experiments on the interaction between protein and DNA indicated that the StHsfB5 protein can directly bind to the promoters of target genes small Hsps (sHsp17.6, sHsp21, and sHsp22.7) and Hsp80, and then induce the expressions of these target genes. All these results showed that StHsfB5 may be a coactivator that promotes potato heat resistance ability by directly inducing the expression of its target genes sHsp17.6, sHsp21, sHsp22.7, and Hsp80.


Assuntos
Proteínas de Ligação a DNA , Solanum tuberosum , Proteínas de Ligação a DNA/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Sequência de Aminoácidos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Resposta ao Choque Térmico/genética , Plantas/metabolismo , Regulação da Expressão Gênica de Plantas
19.
Nat Commun ; 14(1): 7420, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37973875

RESUMO

Responses of cells to stimuli are increasingly discovered to involve the binding of sequence-specific transcription factors outside of known target genes. We wanted to determine to what extent the genome-wide binding and function of a transcription factor are shaped by the cell type versus the stimulus. To do so, we induced the Heat Shock Response pathway in two different cancer cell lines with two different stimuli and related the binding of its master regulator HSF1 to nascent RNA and chromatin accessibility. Here, we show that HSF1 binding patterns retain their identity between basal conditions and under different magnitudes of activation, so that common HSF1 binding is globally associated with distinct transcription outcomes. HSF1-induced increase in DNA accessibility was modest in scale, but occurred predominantly at remote genomic sites. Apart from regulating transcription at existing elements including promoters and enhancers, HSF1 binding amplified during responses to stimuli may engage inactive chromatin.


Assuntos
Proteínas de Ligação a DNA , Neoplasias , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Fatores de Transcrição/metabolismo , Resposta ao Choque Térmico/genética , Cromatina/genética , Neoplasias/genética
20.
Ecotoxicol Environ Saf ; 266: 115571, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37837696

RESUMO

BACKGROUND: Cadmium toxicity has been associated with disruption of protein homeostasis by interfering with protein folding processes. Heat shock factor 1 (HSF1) coordinates the rapid and extensive cellular response to maintain proteomic balance facing the challenges from many environmental stressors. Thus, we suspect that HSF1 may shield cells from cadmium toxicity by conserving proteome integrity. RESULTS: Here, we demonstrate that cadmium, a highly poisonous metal, induces aggregation of cytosolic proteins in human cells, which disrupts protein homeostasis and activates HSF1. Cadmium exposure increases HSF1's phosphorylation, nuclear translocation and DNA bindings. Aside from this, HSF1 goes through liquid-liquid phase separation to form small nuclear condensates upon cadmium exposure. A specific regulatory domain of HSF1 is critical for HSF1's phase separation capability. Most importantly, human cells with impaired HSF1 are sensitized to cadmium, however, cells with overexpressed HSF1 are protected from cadmium toxicity. Overexpression of HSF1 in human cells reduces protein aggregates, amyloid fibrils and DNA damages to antagonize cadmium toxicity. CONCLUSIONS: HSF1 protects cells from cadmium toxicity by governing the integrity of both proteome and genome. Similar mechanisms may enable HSF1 to alleviate cellular toxicity caused by other heavy metals. HSF1's role in cadmium exposure may provide important insights into the toxic effects of heavy metals on human cells and body organs, allowing us to better manage heavy metal poisoning.


Assuntos
Cádmio , Proteínas de Ligação a DNA , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Proteoma/metabolismo , Proteômica
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