Function Of Heat Shock Proteins Research Articles

Heat Shock Proteins: Important Helpers for the Development, Maintenance and Regeneration of Skeletal Muscles

The skeletal muscle is a highly plastic tissue that shows a remarkable adaptive capacity in response to acute and resistance exercise, and modifies its composition to adapt to use and disuse, a process referred to as muscle plasticity. Heat shock proteins (HSPs), a class of evolutionarily conserved molecular chaperones, have been implicated in the regulation of skeletal muscle plasticity. Here, we summarize key findings supporting the notion that HSPs are important components required to maintain skeletal muscle integrity and functionality. HSPs participate in the transcriptional program required for myogenesis and are activated following muscle exercise and injury. Their dysfunction, either as a consequence of improper expression or genetic mutations, contributes to muscle atrophy and leads to the development of myopathies and peripheral motor neuropathies. Denervation/reinnervation and repeated rounds of nerve degeneration/regeneration have been observed in motor neuropathies, suggesting that an imbalance in HSP expression and function may impair the repair of the neuromuscular junctions. Boosting HSP activity may help preventing muscle atrophy by promoting muscle differentiation and helping the repair of NMJs. Boosting HSP function may also help to combat the development of rhabdomyosarcoma (RMS), a highly aggressive type of pediatric soft tissue sarcoma whose cells have skeletal muscle features but are unable to fully differentiate into skeletal muscle cells.

Mode of Action of Heat Shock Protein (HSP) Inhibitors against Viruses through Host HSP and Virus Interactions.

Misfolded proteins after stress-induced denaturation can regain their functions through correct re-folding with the aid of molecular chaperones. As a molecular chaperone, heat shock proteins (HSPs) can help client proteins fold correctly. During viral infection, HSPs are involved with replication, movement, assembly, disassembly, subcellular localization, and transport of the virus via the formation of macromolecular protein complexes, such as the viral replicase complex. Recent studies have indicated that HSP inhibitors can inhibit viral replication by interfering with the interaction of the virus with the HSP. In this review, we describe the function and classification of HSPs, the transcriptional mechanism of HSPs promoted by heat shock factors (HSFs), discuss the interaction between HSPs and viruses, and the mode of action of HSP inhibitors at two aspects of inhibiting the expression of HSPs and targeting the HSPs, and elaborate their potential use as antiviral agents.

The Emerging Role of Heat Shock Factor 1 (HSF1) and Heat Shock Proteins (HSPs) in Ferroptosis.

Cells employ a well-preserved physiological stress response mechanism, termed the heat shock response, to activate a certain type of molecular chaperone called heat shock proteins (HSPs). HSPs are activated by transcriptional activators of heat shock genes known as heat shock factors (HSFs). These molecular chaperones are categorized as the HSP70 superfamily, which includes HSPA (HSP70) and HSPH (HSP110) families; the DNAJ (HSP40) family; the HSPB family (small heat shock proteins (sHSPs)); chaperonins and chaperonin-like proteins; and other heat-inducible protein families. HSPs play a critical role in sustaining proteostasis and protecting cells against stressful stimuli. HSPs participate in folding newly synthesized proteins, holding folded proteins in their native conformation, preventing protein misfolding and accumulation, and degrading denatured proteins. Ferroptosis is a recently identified type of oxidative iron-dependent cell demise. It was coined recently in 2012 by Stockwell Lab members, who described a special kind of cell death induced by erastin or RSL3. Ferroptosis is characterized by alterations in oxidative status resulting from iron accumulation, increased oxidative stress, and lipid peroxidation, which are mediated by enzymatic and non-enzymatic pathways. The process of ferroptotic cell death is regulated at multiple, and it is involved in several pathophysiological conditions. Much research has emerged in recent years demonstrating the involvement of HSPs and their regulator heat shock factor 1 (HSF1) in ferroptosis regulation. Understanding the machinery controlling HSF1 and HSPs in ferroptosis can be employed in developing therapeutic interventions for ferroptosis occurrence in a number of pathological conditions. Therefore, this review comprehensively summarized the basic characteristics of ferroptosis and the regulatory functions of HSF1 and HSPs in ferroptosis.

Transcriptome analysis of Ganoderma lingzhi (Agaricomycetes) response to Trichoderma hengshanicum infection.

Green mold caused by Trichoderma spp. has become one of the most serious diseases which threatening the production of Ganoderma lingzhi. To understand the possible resistance mechanism of the G. lingzhi response to T. hengshanicum infection, we examined the G. lingzhi transcript accumulation at 0, 12, and 24 h after T. hengshanicum inoculation. The gene expression analysis was conducted on the interaction between G. lingzhi and T. hengshanicum using RNA-seq and digital gene expression (DGE) profiling methods. Transcriptome sequencing indicated that there were 162 differentially expressed genes (DEGs) at three infection time points, containing 15 up-regulated DEGs and 147 down-regulated DEGs. Resistance-related genes thaumatin-like proteins (TLPs) (PR-5s), phenylalanine ammonia-lyase, and Beta-1,3-glucan binding protein were significantly up-regulated. At the three time points of infection, the heat shock proteins (HSPs) genes of G. lingzhi were down-regulated. The down-regulation of HSPs genes led to the inhibition of HSP function, which may compromise the HSP-mediated defense signaling transduction pathway, leading to G. lingzhi susceptibility. Pathway enrichment analyses showed that the main enriched pathways by G. lingzhi after infection were sphingolipid metabolism, ether lipid metabolism, and valine, leucine and isoleucine degradation pathway. Overall, the results described here improve fundamental knowledge of molecular responses to G. lingzhi defense and contribute to the design of strategies against Trichoderma spp.

Expression of Heat Shock Proteins in PBMCs is Altered Upon Exposure to Hypothermic and Hyperthermic Conditions and is Correlated with NF-kB Expression

Exposure to extreme conditions has been reported to catalyze the release and function of heat shock proteins (Hsps). However, little is known about the effects of temperature on the changes in immune cell type-specific expression of Hsps.

Protection of HSP60 in Myzus persicae Treated with Cry7Ab4 Toxin

Heat shock proteins (HSPs) are essential for the survival and development of animals under various stresses. However, little is known about the function of HSPs in insects response to Bacillus thuringiensis (Bt) toxins treatment. Here, we investigated the role of HSP60 in Myzus persicae (M. persicae) treated with an active Cry7Ab4 toxic core. First, we demonstrated the insensitivity of M. persicae to the Cry7Ab4 toxic core through a membrane capsule method. Then, using protein pull-down assay, several putative Cry7Ab4-binding proteins, including HSP60, were identified in an M. persicae nymph. P-loop GTPase Obg-like ATPase-1 (OLA1) was also found to be a Cry2Ab12-binding protein (unpublished data). Subsequent enzymatic and RT-qPCR assays revealed that highly expressed HSP60 removed the enhanced OLA1 activity caused by Cry7Ab4. ELISA analysis confirmed the binding interactions between Cry7Ab4, HSP60, and OLA1. Interestingly, a combination of ELISA and molecular docking analysis further suggested that HSP60 could block the binding interaction between Cry7Ab4 and OLA1 via higher affinity with Cry7Ab4. Besides, the Jun N-terminal kinase (JNK) pathway was found to be activated. Overall, we proposed the model that HSP60 protects M. persicae from Cry7Ab4 toxin. The study implies that HSP60 can be a crucial factor in insect defense against Cry toxins.

Identification of a novel heat shock protein 33 of Pythium insidiosum from the first Chinese skin and subcutaneous Pythiosis

ObjectiveTo predict and analyze the structure and function of heat shock protein 33 by bioinformatics analysis. MethodsThe physical and chemical properties, hydrophilicity (hydrophobicity), transmembrane structure, secondary and tertiary structure, subcellular localization, signal peptide and glycosylation, phosphorylation sites, B cell, helper T (Th) cell epitopes of Hsp protein isolated from Pythium insidiosum were analyzed by corresponding bioinformatics software. ResultsHsp33 was composed of 608 amino acids, and the molecular formula was C2182H3538N624O654S16. Hsp33 was a hydrophilic unstable protein. The protein had no transmembrane domain and signal peptide sequence. Subcellular localization analysis shows that the amino acid was a nuclear protein;α-helix, β-sheet, β-turn and random coil accounted for 43.59%, 14.47%, 5.26% and 36.68%, respectively. There were 14 glycosylation sites and 48 phosphorylation sites. It has T cell and B cell dominant epitopes. TLR9 had the best affinity to HSP33 based on its binding affinity. ConclusionThis study lays the foundation for future research on vaccine construct and also provides clues to explore the pathogenic mechanism of HSP33-TLR9 signal pathway for Pythium insidiosum.

Heat shock proteins and metal ions – Reaction or interaction?

Heat shock proteins (HSPs) are part of the cell’s molecular chaperone system responsible for the proper folding (or refolding) of proteins. They are expressed in cells of a wide variety of organisms, from bacteria and fungi to humans. While some HSPs require metal ions for proper functioning, others are expressed as a response of the organism to either essential or toxic metal ions. Their presence can influence the occurrence of cellular processes, even those as significant as programmed cell death. The development of research methods and structural modeling has enabled increasingly accurate recognition of new HSP functions, including their role in maintaining metal ion homeostasis. Current investigations on the expression of HSPs in response to heavy metal ions include not only the direct effect of these ions on the cell but also analysis of reactive oxygen species (ROS) and the increased production of HSPs with increasing ROS concentration. This minireview contains information about the direct and indirect interactions of heat shock proteins with metal ions, both those of biological importance and heavy metals.

Multiple Targeting of HSP Isoforms to Challenge Isoform Specificity and Compensatory Expression.

Heat shock proteins (HSPs) are molecular chaperones that assist in protein folding, trafficking, and metabolism. Intracellular chaperone functions of HSPs had been well-investigated, but extracellular and exosomal HSPs have been recently found. Exosomal HSPs are intercellularly transferred, while extracellular HSPs play cytokine-like roles called chaperokines. We have shown that exosomal HSPs play key roles in intercellular communication between tongue carcinoma and tumor-associated macrophages in the tumor microenvironment. Notably, HSP90 isoforms consist of HSP90alpha, HSP90beta, mitochondrial TRAP1, and GRP94 in the endoplasmic reticulum. Moreover, many pseudogenes of HSP90 can be transcribed into RNA. Besides, the function of HSP90 is defined by their cochaperones, such as CDC37 or AHA1. Therefore, isoform-specific small interfering RNA (siRNA) is necessary for precisely targeting each HSP90 isoform and cochaperone. Nevertheless, we often encountered compensatory expression of HSP90 isoforms in the knockdown studies. Here, we provide dual and triple knockdown methods to target multiple RNA for challenging isoform-specific roles and compensatory expression of intracellular, extracellular, and exosomal HSPs.

Impaired Heat Shock Protein Expression in Activated T Cells in B-Cell Lymphoma.

Heat shock proteins (HSPs) are molecular chaperones that act in a variety of cellular processes, ensuring protein homeostasis and integrity. HSPs play critical roles in the modulation of various immune cells. However, the role of HSPs in T cell activation is largely unknown. We show that HSPs are upregulated following CD3/CD28 stimulation, suggesting that HSP expression might be regulated via TCR. We found that B-cell lymphoma (BCL) patients have dysregulated expression of intracellular and extracellular HSPs, immune checkpoints PD-1, CTLA-4, and STAT3 in CD3/CD28-activated T cells. Consistent with previous findings, we show that HSP90 inhibition downregulated CD4 and CD8 surface markers in healthy controls and BCL patients. HSP90 inhibition alone or in combination with PD-1 or CTLA-4 inhibitors differentially affected CD4+ and CD8+ T cell degranulation responses when stimulated with allogeneic DCs or CD3/CD28 in BCL patients. Additionally, we showed that HSP90 inhibition does not significantly affect intracellular PD-1 and CTLA-4 expression in CD3/CD28-activated T cells. These findings may provide the basis for the discovery of novel immunological targets for the treatment of cancer patients and improve our understanding of HSP functions in immune cells.

Enhancing the Efficiency of Mild-Temperature Photothermal Therapy for Cancer Assisting with Various Strategies.

Conventional photothermal therapy (PTT) irradiates the tumor tissues by elevating the temperature above 48 °C to exert thermal ablation, killing tumor cells. However, thermal ablation during PTT harmfully damages the surrounding normal tissues, post-treatment inflammatory responses, rapid metastasis due to the short-term mass release of tumor-cellular contents, or other side effects. To circumvent this limitation, mild-temperature photothermal therapy (MTPTT) was introduced to replace PTT as it exerts its activity at a therapeutic temperature of 42-45 °C. However, the significantly low therapeutic effect comes due to the thermoresistance of cancer cells as MTPTT figures out some of the side-effects issues. Herein, our current review suggested the mechanism and various strategies for improving the efficacy of MTPTT. Especially, heat shock proteins (HSPs) are molecular chaperones overexpressed in tumor cells and implicated in several cellular heat shock responses. Therefore, we introduced some methods to inhibit activity, reduce expression levels, and hinder the function of HSPs during MTPTT treatment. Moreover, other strategies also were emphasized, including nucleus damage, energy inhibition, and autophagy mediation. In addition, some therapies, like radiotherapy, chemotherapy, photodynamic therapy, and immunotherapy, exhibited a significant synergistic effect to assist MTPTT. Our current review provides a basis for further studies and a new approach for the clinical application of MTPTT.

Nanoengineering a Zeolitic Imidazolate Framework-8 Capable of Manipulating Energy Metabolism against Cancer Chemo-Phototherapy Resistance.

Chemo-phototherapy has emerged as a promising approach to complement traditional cancer treatment and enhance therapeutic effects. However, it still faces the challenges of drug efflux transporter-mediated chemoresistance and heat shock proteins (HSPs)-mediated phototherapy tolerance, which both depend on an excessive supply of adenosine triphosphate. Therefore, manipulating energy metabolism to impair the expression or function of P-glycoprotein (P-gp) and HSPs may be a prospective strategy to reverse cancer therapeutic resistance. Herein, a chondroitin sulfate (CS)-functionalized zeolitic imidazolate framework-8 (ZIF-8) chemo-phototherapy nanoplatform (CS/ZIF-8@A780/DOX NPs) is rationally designed that is capable of manipulating energy metabolism against cancer therapeutic resistance by integrating the photosensitizer IR780iodide (IR780)-conjugated atovaquone (ATO) (A780) and the chemotherapeutic agent doxorubicin (DOX). Mechanistically, ATO and zinc ions that are released in the acidic tumor microenvironment can lead to systematic energy exhaustion through disturbing mitochondrial electron transport and the glycolysis process, thus suppressing the activity of P-gp and HSP70, respectively. In addition, CS is used on the surface of ZIF-8@A780/DOX NPs to improve the targeting capability to tumor tissues. These data provide an efficient strategy for manipulating energy metabolism for cancer treatment, especially for overcoming cancer chemo-phototherapy resistance.

The hsp70 new functions as a regulator of reproduction both female and male in Ophraella communa.

Heat shock proteins (Hsps) function as molecular chaperones that enable organisms to withstand stress and maintain normal life activities. In this study, we identified heat shock protein 70 (encoded by hsp70), which exhibits a higher expression in the mature male testis than in the unmature testis of Ophraella communa. Tissue expression profile revealed that Ochsp70 levels in males were highest in the testis, whereas those in females were highest in the head. Moreover, the expression of Ochsp70 was found to be significantly induced in female bursa copulatrix after mating. Double-stranded RNA dsOchsp70 was injected into males to performance RNA interference, which significantly decreased the male Ochsp70 expression levels within 20 d post-injection, whereas no effect was observed on the Ochsp70 expression level in the females after mating with dsOchsp70-injected males. However, significant downregulation of female fertility was marked simultaneously. Furthermore, knockdown of female Ochsp70 expression also led to a significant reduction in fertility. Finally, comparative transcriptomic analysis identified glucose dehydrogenase and insulin-like growth factor binding protein as putative downstream targets of Ochsp70. Overall, we deduced that Ochsp70 is an indispensable gene and a potential male mating factor in O. communa, which regulates reproduction.

The role of heat shock proteins in metastatic colorectal cancer: A review.

Heat shock proteins (HSPs) are a large molecular chaperone family classified by their molecular weights, including HSP27, HSP40, HSP60, HSP70, HSP90, and HSP110. HSPs are likely to have antiapoptotic properties and participate actively in various processes such as tumor cell proliferation, invasion, metastases, and death. In this review, we discuss comprehensively the functions of HSPs associated with the progression of colorectal cancer (CRC) and metastasis and resistance to cancer therapy. Taken together, HSPs have numerous clinical applications as biomarkers for cancer diagnosis and prognosis and potential therapeutic targets for CRC and its related metastases.

Heat shock proteins and viral infection.

Heat shock proteins (HSPs) are a kind of proteins which mostly found in bacterial, plant and animal cells, in which they are involved in the monitoring and regulation of cellular life activities. HSPs protect other proteins under environmental and cellular stress by regulating protein folding and supporting the correctly folded structure of proteins as chaperones. During viral infection, some HSPs can have an antiviral effect by inhibiting viral proliferation through interaction and activating immune pathways to protect the host cell. However, although the biological function of HSPs is to maintain the homeostasis of cells, some HSPs will also be hijacked by viruses to help their invasion, replication, and maturation, thereby increasing the chances of viral survival in unfavorable conditions inside the host cell. In this review, we summarize the roles of the heat shock protein family in various stages of viral infection and the potential uses of these proteins in antiviral therapy.

FOXM1 regulates glycolysis and energy production in multiple myeloma

The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.

Hsc70 interacts with KCNA5 to promote the proliferation of granulosa cells in polycystic ovarian syndrome

Purpose: To investigate the function and interaction of heat-shock cognate protein 70 (Hsc70) and potassium voltage-gated channel subfamily A member 5 (KCNA5) in polycystic ovary syndrome (PCOS).Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were used to measure Hsc70 and KCNA5 expression in PCOS. The effect of Hsc70 on granulosa cell apoptosis was determined by flow cytometry. Cell counting kit-8 (CCK-8) and colony formation assay were used to assess the impact of Hsc70 on cell proliferation, while the interaction of Hsc70 with KCNA5 were evaluated by Western blot, CCK-8, and colony formation assay, respectively.Results: Hsc70 expression was upregulated in PCOS compared to the control (p < 0.05). In granulosa cells, Hsc70 overexpression promoted cell proliferation but inhibited apoptosis (p < 0.05), whereas Hsc70 knockdown suppressed cell proliferation and promoted apoptosis (p < 0.05). Furthermore, KCNA5 expression was downregulated in PCOS (p < 0.05) and was negatively correlated with Hsc70 expression. KCNA5 knockdown promoted granulosa cell proliferation and also attenuated the Hsc70 knockdown-mediated inhibition of granulosa cell proliferation (p < 0.05).Conclusion: Hsc70 promotes granulosa cell proliferation by interacting with KCNA5, further defining the molecular mechanism behind PCOS.

Forcing the Antitumor Effects of HSPs Using a Modulated Electric Field.

The role of Heat Shock Proteins (HSPs) is a “double-edged sword” with regards to tumors. The location and interactions of HSPs determine their pro- or antitumor activity. The present review includes an overview of the relevant functions of HSPs, which could improve their antitumor activity. Promoting the antitumor processes could assist in the local and systemic management of cancer. We explore the possibility of achieving this by manipulating the electromagnetic interactions within the tumor microenvironment. An appropriate electric field may select and affect the cancer cells using the electric heterogeneity of the tumor tissue. This review describes the method proposed to effect such changes: amplitude-modulated radiofrequency (amRF) applied with a 13.56 MHz carrier frequency. We summarize the preclinical investigations of the amRF on the HSPs in malignant cells. The preclinical studies show the promotion of the expression of HSP70 on the plasma membrane, participating in the immunogenic cell death (ICD) pathway. The sequence of guided molecular changes triggers innate and adaptive immune reactions. The amRF promotes the secretion of HSP70 also in the extracellular matrix. The extracellular HSP70 accompanied by free HMGB1 and membrane-expressed calreticulin (CRT) form damage-associated molecular patterns encouraging the dendritic cells’ maturing for antigen presentation. The process promotes CD8+ killer T-cells. Clinical results demonstrate the potential of this immune process to trigger a systemic effect. We conclude that the properly applied amRF promotes antitumor HSP activity, and in situ, it could support the tumor-specific immune effects produced locally but acting systemically for disseminated cells and metastatic lesions.

Immunological aspects of heat shock protein functions and their significance in the development of cancer vaccines

The primary function of intracellular heat shock proteins (HSPs) is to protect the cell by suppressing the effects of va­rious stress factors by either refolding misfolded proteins or blocking apoptosis. After neoplastic transformation, cells overexpress HSPs, which act as factors promoting the neoplastic process by stabilizing proteins responsible for carci­nogenesis, however, HSPs can be released into the extracellular environment where they act as important modulators of the immune response. In a tumor microenvironment, extracellular HSPs are able to induce a pro- or anti-neoplastic response, using various mechanisms of affecting immune cells, The study of the role of extracellular HSPs in immuno­modulation processes is a very important direction in the search for new methods of cancer treatment. This review summarizes reports on the use of HSPs in immunotherapeutic cancer strategies, in particular in cancer vaccine design.

Minimal Yet Powerful: The Role of Archaeal Small Heat Shock Proteins in Maintaining Protein Homeostasis.

Small heat shock proteins (sHsp) are a ubiquitous group of ATP-independent chaperones found in all three domains of life. Although sHsps in bacteria and eukaryotes have been studied extensively, little information was available on their archaeal homologs until recently. Interestingly, archaeal heat shock machinery is strikingly simplified, offering a minimal repertoire of heat shock proteins to mitigate heat stress. sHsps play a crucial role in preventing protein aggregation and holding unfolded protein substrates in a folding-competent form. Besides protein aggregation protection, archaeal sHsps have been shown recently to stabilize membranes and contribute to transferring captured substrate proteins to chaperonin for refolding. Furthermore, recent studies on archaeal sHsps have shown that environment-induced oligomeric plasticity plays a crucial role in maintaining their functional form. Despite being prokaryotes, the archaeal heat shock protein repository shares several features with its highly sophisticated eukaryotic counterpart. The minimal nature of the archaeal heat shock protein repository offers ample scope to explore the function and regulation of heat shock protein(s) to shed light on their evolution. Moreover, similar structural dynamics of archaeal and human sHsps have made the former an excellent system to study different chaperonopathies since archaeal sHsps are more stable under in vitro experiments.