Regulation Of Hsp70 Research Articles

Transcriptomics and phenotypic analysis of OTOF gene knockdown in Zebrafish mediated by CRISPR/Cas9.

Transcriptomics and phenotypic analysis of OTOF gene knockdown in Zebrafish mediated by CRISPR/Cas9.

The Expression Levels of Heat Shock Protein 90 (HSP90) in Galleria mellonella Following Infection with the Entomopathogenic Nematode Steinernema carpocapsae and Its Symbiotic Bacteria Xenorhabdus nematophila.

Heat shock proteins (HSPs), particularly HSP90, play a vital role in insect responses to environmental and biotic stresses by maintaining protein stability and supporting immune defenses. This study explores HSP90 regulation in Galleria mellonella larvae following exposure to the nematode Steinernema carpocapsae and its symbiotic bacterium Xenorhabdus nematophila. Exposure to live nematodes caused slight changes in HSP90 expression, while non-viable nematodes had no effect, suggesting that nematode secretions or symbiotic bacteria do not directly influence HSP90 levels. However, nematodes with altered surface properties significantly increased HSP90 expression. X. nematophila also moderately elevated HSP90 levels but this effect disappeared when weakly bound surface proteins were removed. Interestingly, under thermal stress, live nematodes reduced heat-induced HSP90 expression, whereas surface-treated nematodes enhanced it. These findings suggest that HSP90 modulation is influenced by biological control agents, highlighting a potential link between HSP90 and immune detection of invaders. This interaction may be crucial in adapting biological control strategies in response to climate change. Further research is needed to clarify HSP activation pathways, host immune interactions, and mechanisms of entomopathogen immune evasion, particularly under varying environmental temperatures, to enhance bioinsecticide efficacy.

Hsp90: Bringing it all together.

Hsp90: Bringing it all together.

Insights into the Allosteric Regulation of Human Hsp90 Revealed by NMR Spectroscopy.

Human heat shock protein 90 (Hsp90) is one of the most important chaperones that play a role in the late stages of protein folding. Errors in the process of the chaperone cycle can lead to diseases such as cancer and neurodegenerative diseases. Therefore, the activity of Hsp90 must be carefully regulated. One of the possibilities is allosteric regulation by its natural allosteric modulators-nucleotides, co-chaperones and client proteins-and synthetic small-molecule allosteric modulators, such as those targeting the middle domain or the C-terminal domain (CTD) of Hsp90. Since no experimentally determined structure of a small-molecule allosteric modulator bound to the CTD of human Hsp90 has yet been obtained, the challenge for a structure-based design of allosteric modulators remains. Solution nuclear magnetic resonance (NMR) spectroscopy could be utilized to overcome these problems. The main aim of this review article is to discuss how solution NMR techniques, especially protein-based, and the advanced isotope labeling of proteins have been used to investigate the allosteric regulation of the cytosolic isoforms of human Hsp90 with allosteric modulators. This article provides the basis for planning future NMR experiments, with the aim of gaining insights into allosteric sites and the mechanisms of allosteric regulation.

Feedback control of the heat shock response by spatiotemporal regulation of Hsp70.

Cells maintain homeostasis via dynamic regulation of stress response pathways. Stress pathways transiently induce response regulons via negative feedback loops, but the extent to which individual genes provide feedback has not been comprehensively measured for any pathway. Here, we disrupted the induction of each gene in the Saccharomyces cerevisiae heat shock response (HSR) and quantified cell growth and HSR dynamics following heat shock. The screen revealed a core feedback loop governing the expression of the chaperone Hsp70 reinforced by an auxiliary feedback loop controlling Hsp70 subcellular localization. Mathematical modeling and live imaging demonstrated that multiple HSR targets converge to promote Hsp70 nuclear localization via its release from cytosolic condensates. Following ethanol stress, a distinct set of factors similarly converged on Hsp70, suggesting that nonredundant subsets of the HSR regulon confer feedback under different conditions. Flexible spatiotemporal feedback loops may broadly organize stress response regulons and expand their adaptive capacity.

Potential synergistic regulation of hsp70 and antioxidant enzyme genes in Pyropia yezoensis under high temperature stress

Potential synergistic regulation of hsp70 and antioxidant enzyme genes in Pyropia yezoensis under high temperature stress

The Efficacy of Hyperbaric Oxygen Therapy in COVID-19 Patients with Cytokine Storm by Reducing Proinflammatory Cytokine Levels through HSP-70 Regulation: A Systematic Review

The Efficacy of Hyperbaric Oxygen Therapy in COVID-19 Patients with Cytokine Storm by Reducing Proinflammatory Cytokine Levels through HSP-70 Regulation: A Systematic Review

Protective effects of L-theanine and dihydromyricetin on reproductive function in male mice under heat stress.

Heat stress can impair the male reproductive function. L-Theanine and dihydromyricetin have biological activities against heat stress; however, their effects on reproductive function in heat-stressed males are unclear. In this study, male mice were given L-theanine, dihydromyricetin, or a combination of both for 28 days, followed by 2 h of heat stress daily for 7 days. All interventions alleviated heat stress-induced testicular damage, improving the testicular organ index, sperm density, acrosome integrity, sperm deformity rate, and hormone levels. Treatment increased the antioxidant enzyme activity and decreased the markers of oxidative and inflammatory stress in the testes. A combination dose of 200 + 200 mg kg-1 d-1 showed the best protective effect. The potential mechanism involves the regulation of HSP27 and HSP70, which regulate the levels of reproductive hormones through the StAR/Cyp11a1/Hsd3b1/Cyp17a1/Hsd17b3 pathway, alleviate inflammation and oxidative stress through the P38/NF-κB/Nrf2/HO-1 pathway, and regulate the Bcl-2/Fas/Caspase3 apoptotic pathway. Overall, L-theanine and dihydromyricetin may play a protective role against heat stress-induced reproductive dysfunction, suggesting their potential use in heat stress-resistant foods.

Pharmacological Modulation of Heat Shock Proteins for Enhancing Thermotolerance and Immune Resilience in Heat-Stressed Livestock

Background: Heat stress reduces immunological resilience and cattle output, hence efforts to improve thermotolerance are needed. This study thus aimed to increase thermotolerance and immunological function in heat-stressed cows by pharmacological regulation of HSP70 with resveratrol, quercetin, and geranylgeranyl acetone (GGA). Methods: One hundred and twenty cows aged 2–5 years were involved in this cross-sectional study carried out at Gomal University, Dera Ismail Khan between February 2024 and October 2024. Four groups comprised cows: control, resveratrol (200 mg/day), quercetin (300 mg/day), and GGA (100 mg/day). Treatments were given for sixty days then under thirty-day observation. Rectal temperature, HSP70 expression, antioxidant enzyme activities, and inflammatory markers (IL-6, TNF-α) among physiological, biochemical, and immunological parameters were examined. Results: Treated groups showed notable lower rectal temperature than the control (p < 0.05). Day 60 saw quercetin and GGA reach the lowest temperatures—38.4 ± 0.2°C and 38.5 ± 0.2°C—against the control, 39.0 ± 0.3°C. By day 60, HSP70 concentrations rose dramatically and peaked in the GGA group (p = 0.001) at 3.2 ± 0.3 ng/mL. With SOD (11.5 ± 0.6 U/mg) and catalase (15.3 ± 0.7 U/mg), the GGA group had the highest antioxidant activity (p < 0.05). With the GGA group displaying 9.3 ± 0.7 pg/mL and 16.8 ± 0.8 pg/mL respectively, IL-6 and TNF-α levels likewise dropped (p < 0.05). Conclusion: Heat-stressed cows' thermotolerance, antioxidant defenses and immunological control are improved by pharmacological manipulation of HSP70 with quercetin and GGA. These agents deserve more long-term research since they showed good ways to reduce heat stress in animals.

Effects of Inhibition of IKK Kinase Phosphorylation On the Cellular Defence System and HSP90 Activity

The present study was conceived to examine the effects of inhibition of BMS-345541 mediated IKK kinase phosphorylation on the cellular defence system as well as on anti-inflammatory response and HSP90 activity. The analysis was conducted in A549 cell line, since such cells carry a homozygous Keap1 mutation (G333C) that alters its interaction with Nrf2. Recent data have highlighted that Keap1, HSP90 protein and IKK kinase interact reciprocally and particularly Keap1 protein is involved in HSP90 and anti-oxidative pathway regulation. The activities of COX2 and HO1 were investigated by real time and immunoblot analysis along with the synthesis and activity of inducible forms of heat shock protein HSP90. Pre-treatment with IKK kinase inhibitor proved to be a protective means to lower the activity of inflammatory cascade, so preventing the formation of excessive amounts of pro-inflammatory molecules. The inhibitor of IKK kinase BMS-345541 was added to cultured A549 cells before the Escherichia coli lipopolysaccharide (LPS) addition. The viability of the cells was determined after 1–24 h incubation with BMS-345541 at concentrations ranging from 1,25–5 µM. It was found that 1 µM concentration does not significantly affected cell viability (data not shown). As a result, the treatment with 1 μM of BMS-345541 induces the inhibition of IKK phosphorylation. In the A549 cells treated with BMS-345541 and LPS, COX2 activity is not induced: mRNA and protein levels have not increased, while there is an increase in the level of HSP90, HO1 proteins and mRNA. The results suggest that the IKK inhibition is effective in the reduction of the inflammatory response thanks to mechanisms involving both the heat shock cellular defense system and the antioxidative pathway.Graphical

The implications of exercise in Drosophila melanogaster: insights into Akt/p38 MAPK/Nrf2 pathway associated with Hsp70 regulation in redox balance maintenance.

This study investigated the potential effects of exercise on the responses of energy metabolism, redox balance maintenance, and apoptosis regulation in Drosophila melanogaster to shed more light on the mechanisms underlying the increased performance that this emerging exercise model provides. Three groups were evaluated for seven days: the control (no exercise or locomotor limitations), movement-limited flies (MLF) (no exercise, with locomotor limitations), and EXE (with exercise, no locomotor limitations). The EXE flies demonstrated greater endurance-like tolerance in the swimming test, associated with increased citrate synthase activity, lactate dehydrogenase activity and lactate levels, and metabolic markers in exercise. Notably, the EXE protocol regulated the Akt/p38 MAPK/Nrf2 pathway, which was associated with decreased Hsp70 activation, culminating in glutathione turnover regulation. Moreover, reducing the locomotion environment in the MLF group decreased endurance-like tolerance and did not alter citrate synthase activity, lactate dehydrogenase activity, or lactate levels. The MLF treatment promoted a pro-oxidant effect, altering the Akt/p38 MAPK/Nrf2 pathway and increasing Hsp70 levels, leading to a poorly-regulated glutathione system. Lastly, we demonstrated that exercise could modulate major metabolic responses in Drosophila melanogaster aerobic and anaerobic metabolism, associated with apoptosis and cellular redox balance maintenance in an emergent exercise model.

Aha1 regulates Hsp90’s conformation and function in a stoichiometry-dependent way

Aha1 regulates Hsp90’s conformation and function in a stoichiometry-dependent way

Tanespimycin and rapamycin exhibit antifungal activity against Colletotrichum gloeosporioides and enhance mango resistance to anthracnose via differentially modulating heat shock response

Tanespimycin and rapamycin exhibit antifungal activity against Colletotrichum gloeosporioides and enhance mango resistance to anthracnose via differentially modulating heat shock response

Differential expression profile of genes involved in the immune response associated to progression of chronic Chagas disease.

Patients with chronic Chagas disease present marked clinical and immunological heterogeneity. During the disease, multiple immune mechanisms are activated to fight the parasite. The purpose of this study was to investigate the expression patterns of genes involved in relevant immunological processes throughout the disease in patients with chronic Chagas disease. High-throughput RT-qPCR with QuantStudio 12K Flex real-time PCR system was used to evaluate the expression of 106 immune-related genes in PBMC from a cohort of cardiac Chagas disease patients (CCC I), asymptomatic patients (IND) and healthy donors (HD) after being stimulated with T. cruzi soluble antigens. Principal component analysis (PCA), cluster analysis and volcano plots were used to identify differentially expressed genes. In addition, gene set enrichment analysis (GSEA) was employed to identify the enriched immunological pathways in which these genes are involved. PCA revealed the existence of a statistically divergent expression profile of the 36 genes correlated with PC1 between CCC I patients and HD (p < 0.0001). Differential gene expression analysis revealed upregulation of 41 genes (expression fold-change > 1.5) and downregulation of 14 genes (expression fold-change < 0.66) (p = 8.4x10-13 to p = 0.007) in CCC I patients versus HD. Furthermore, significant differences in the expression level of specific genes have been identified between CCC I and IND patients (8 up and 1 downregulated). GSEA showed that several upregulated genes in CCC I patients participate in immunological pathways such as antigen-dependent B cell activation, stress induction of HSP regulation, NO2-dependent IL12 pathway in NK cells, cytokines-inflammatory response and IL-10 anti-inflammatory signaling. Cardiac Chagas disease patients show an antigen-specific differential gene expression profile in which several relevant immunological pathways seem to be activated. Assessment of gene expression profiles reveal unique insights into the immune response that occurs along chronic Chagas disease.

Cadmium exposure promotes ferroptosis by upregulating Heat Shock Protein 70 in vascular endothelial damage of zebrafish

Cadmium exposure promotes ferroptosis by upregulating Heat Shock Protein 70 in vascular endothelial damage of zebrafish

The effects of Pandanus tectorius leaf extract on the resistance of White-leg shrimp Penaeus vannamei towards pathogenic Vibrio parahaemolyticus

The effects of Pandanus tectorius leaf extract on the resistance of White-leg shrimp Penaeus vannamei towards pathogenic Vibrio parahaemolyticus

Analysis of signaling cascades from myeloma cells treated with pristimerin.

Analysis of signaling cascades from myeloma cells treated with pristimerin.

Detecting Posttranslational Modifications of Hsp90 Isoforms.

The molecular chaperone heat shock protein 90 (Hsp90) is essential in eukaryotes. Hsp90 chaperones proteins that are important determinants of multistep carcinogenesis. There are multiple Hsp90 isoforms including the cytosolic Hsp90α and Hsp90β as well as GRP94 located in the endoplasmic reticulum and TRAP1 in the mitochondria. The chaperone function of Hsp90 is linked to its ability to bind and hydrolyze ATP. Co-chaperones and posttranslational modifications (such as phosphorylation, SUMOylation, and ubiquitination) are important for Hsp90 stability and regulation of its ATPase activity. Both mammalian and yeast cells can be used to express and purify Hsp90 and TRAP1 and also detect post-translational modifications by immunoblotting.

Impact of Co-chaperones and Posttranslational Modifications Toward Hsp90 Drug Sensitivity.

Posttranslational modifications (PTMs) regulate myriad cellular processes by modulating protein function and protein-protein interaction. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone whose activity is responsible for the stabilization and maturation of more than 300 client proteins. Hsp90 is a substrate for numerous PTMs, which have diverse effects on Hsp90 function. Interestingly, many Hsp90 clients are enzymes that catalyze PTM, demonstrating one of the several modes of regulation of Hsp90 activity. Approximately 25 co-chaperone regulatory proteins of Hsp90 impact structural rearrangements, ATP hydrolysis, and client interaction, representing a second layer of influence on Hsp90 activity. A growing body of literature has also established that PTM of these co-chaperones fine-tune their activity toward Hsp90; however, many of the identified PTMs remain uncharacterized. Given the critical role of Hsp90 in supporting signaling in cancer, clinical evaluation of Hsp90 inhibitors is an area of great interest. Interestingly, differential PTM and co-chaperone interaction have been shown to impact Hsp90 binding to its inhibitors. Therefore, understanding these layers of Hsp90 regulation will provide a more complete understanding of the chaperone code, facilitating the development of new biomarkers and combination therapies.

Ydj1 interaction at nucleotide-binding-domain of yeast Ssa1 impacts Hsp90 collaboration and client maturation.

Hsp90 constitutes one of the major chaperone machinery in the cell. The Hsp70 assists Hsp90 in its client maturation though the underlying basis of the Hsp70 role remains to be explored. In the present study, using S. cerevisiae strain expressing Ssa1 as sole Ssa Hsp70, we identified novel mutations in the nucleotide-binding domain of yeast Ssa1 Hsp70 (Ssa1-T175N and Ssa1-D158N) that adversely affect the maturation of Hsp90 clients v-Src and Ste11. The identified Ssa1 amino acids critical for Hsp90 function were also found to be conserved across species such as in E.coli DnaK and the constitutive Hsp70 isoform (HspA8) in humans. These mutations are distal to the C-terminus of Hsp70, that primarily mediates Hsp90 interaction through the bridge protein Sti1, and proximal to Ydj1 (Hsp40 co-chaperone of Hsp70 family) binding region. Intriguingly, we found that the bridge protein Sti1 is critical for cellular viability in cells expressing Ssa1-T175N (A1-T175N) or Ssa1-D158N (A1-D158N) as sole Ssa Hsp70. The growth defect was specific for sti1Δ, as deletion of none of the other Hsp90 co-chaperones showed lethality in A1-T175N or A1-D158N. Mass-spectrometry based whole proteome analysis of A1-T175N cells lacking Sti1 showed an altered abundance of various kinases and transcription factors suggesting compromised Hsp90 activity. Further proteomic analysis showed that pathways involved in signaling, signal transduction, and protein phosphorylation are markedly downregulated in the A1-T175N upon repressing Sti1 expression using doxycycline regulatable promoter. In contrast to Ssa1, the homologous mutations in Ssa4 (Ssa4-T175N/D158N), the stress inducible Hsp70 isoform, supported cell growth even in the absence of Sti1. Overall, our data suggest that Ydj1 competes with Hsp90 for binding to Hsp70, and thus regulates Hsp90 interaction with the nucleotide-binding domain of Hsp70. The study thus provides new insight into the Hsp70-mediated regulation of Hsp90 and broadens our understanding of the intricate complexities of the Hsp70-Hsp90 network.