Showing papers on "Heat shock protein published in 2017"
TL;DR: The administration of HSPA12B siRNA aggravated lung pathological injury, upregulated pro-inflammatory cytokine expression, and increased myeloperoxidase activity, neutrophil infiltration, pulmonary edema, and pulmonary endothelial cell apoptosis protected against sepsis-induced ALI.
Abstract: Background: Pulmonary endothelial injury is a critical process in the pathogenesis of acute lung injury (ALI) during sepsis Heat shock protein A12B (HSPA12B) is
2,141 citations
TL;DR: Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
Abstract: The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
1,016 citations
TL;DR: The roles of major HSPs in cancer biology and pharmacology are reviewed to comprehensively review the role they play in the molecular mechanisms leading to cancer development and metastasis.
431 citations
TL;DR: The role of HSPs/chaperones in regulating diverse signalling pathways is illustrated and several basic principles that should be considered for engineering multiple stress resistance in crops through the HSP/ chaperone network are discussed.
Abstract: Crop yield has been greatly enhanced during the last century. However, most elite cultivars are adapted to temperate climates and are not well suited to more stressful conditions. In the context of climate change, stress resistance is a major concern. To overcome these difficulties, scientists may help breeders by providing genetic markers associated with stress resistance. However, multistress resistance cannot be obtained from the simple addition of single stress resistance traits. In the field, stresses are unpredictable and several may occur at once. Consequently, the use of single stress resistance traits is often inadequate. Although it has been historically linked with the heat stress response, the heat-shock protein (HSP)/chaperone network is a major component of multiple stress responses. Among the HSP/chaperone 'client proteins', many are primary metabolism enzymes and signal transduction components with essential roles for the proper functioning of a cell. HSPs/chaperones are controlled by the action of diverse heat-shock factors, which are recruited under stress conditions. In this review, we give an overview of the regulation of the HSP/chaperone network with a focus on Arabidopsis thaliana. We illustrate the role of HSPs/chaperones in regulating diverse signalling pathways and discuss several basic principles that should be considered for engineering multiple stress resistance in crops through the HSP/chaperone network.
421 citations
TL;DR: The roles of some of the important HSPs in cancer are reviewed, and how targeting them could be efficacious, especially when traditional cancer therapies fail are reviewed.
Abstract: Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of “client” proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.
365 citations
TL;DR: Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.
Abstract: In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tu...
246 citations
TL;DR: The role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD is discussed.
Abstract: TThe accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer’s disease (AD). Assembles of beta-amyloid (Aβ) peptide – either soluble (oligomers - Aβ) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a C. elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on Alzheimer’s disease.
245 citations
TL;DR: It is proposed that careful induction of HSPs in HID and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer.
Abstract: Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body. HSPs are known to modulate the effects of inflammation cascades leading to the endogenous generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of HIDs and cancer. We propose that careful induction of HSPs in HIDs and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer.
196 citations
TL;DR: Accumulating evidence now shows that HSF1, the central player in the HSR, is regulated according to specific cellular requirements through cell-aut autonomous and non-autonomous signals, and directs transcriptional programs distinct from the H SR during development and in carcinogenesis.
193 citations
TL;DR: HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2, and a combination of these proteins could strongly predict the poor prognosis of H CC patients.
Abstract: Heat shock protein 90 (HSP90) functions as a well-known onco-protein to regulate protein conformation, stability and degradation. Pyruvate kinase M2 (PKM2), a critical regulator of the metabolism, growth and metastasis of cancer cells, has been confirmed to be overexpressed in various human cancer including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the oncogenic functions of HSP90 and PKM2 overexpression in HCC remain unknown. The expression of HSP90 and PKM2 in HCC specimens and cells were detected by immunoblotting and immunostaining. The interaction between HSP90 and PKM2 was confirmed by tandem affinity purification, co-immunoprecipitation and Glutathione S transferase (GST)-pulldown assay. In this study, we found that HSP90 could bind to PKM2 and subsequently increased PKM2 abundance in HCC cells. Immunohistochemistry (IHC) staining showed that HSP90 level was positively correlated with PKM2 level in HCC tissues. Mechanistically, HSP90 was found to increase the phosphorylation of PKM2 at Thr-328. Protein kinase glycogen synthase kinase-3β (GSK-3β) formed a protein complex with HSP90 and PKM2, and directly mediated Thr-328 phosphorylation of PKM2 induced by HSP90. Thr-328 phosphorylation was critical for maintaining PKM2 stability and its biological functions in regulating glycolysis, mitochondria respiration, proliferation and apoptosis. Functionally, we found that HSP90 promoted the glycolysis and proliferation and inhibited apoptosis of HCC cells in a PKM2 dependent manner. In vivo experiments disclosed that PKM2 was required for the promoting effects of HSP90 on the growth of HCC cells in mice. Furthermore, we demonstrated that positive expression of HSP90 and PKM2 was correlated with poor clinicopathological features including high alpha fetoprotein (AFP) level, large tumor size, portal vein tumor thrombus (PVTT) and advanced tumor-node-metastasis (TNM) stage. Furthermore, we demonstrated that positive expression of HSP90 and PKM2, and a combination of these proteins could strongly predict the poor prognosis of HCC patients. We suggest that HSP90 potentiates the glycolysis and proliferation, reduces the apoptosis and thus enhances the growth of HCC cells through PKM2.
131 citations
TL;DR: The structure and function of the mammalian HSF1 is discussed and its regulation by post‐translational modifications (phosphorylation, sumoylation and acetylation), proteasomal degradation, and small‐molecule activators and inhibitors are discussed.
Abstract: Living organisms are endowed with the capability to tackle various forms of cellular stress due to the presence of molecular chaperone machinery complexes that are ubiquitous throughout the cell. During conditions of proteotoxic stress, the transcription factor heat shock factor 1 (HSF1) mediates the elevation of heat shock proteins, which are crucial components of the chaperone complex machinery and function to ameliorate protein misfolding and aggregation and restore protein homeostasis. In addition, HSF1 orchestrates a versatile transcriptional programme that includes genes involved in repair and clearance of damaged macromolecules and maintenance of cell structure and metabolism, and provides protection against a broad range of cellular stress mediators, beyond heat shock. Here, we discuss the structure and function of the mammalian HSF1 and its regulation by post-translational modifications (phosphorylation, sumoylation and acetylation), proteasomal degradation, and small-molecule activators and inhibitors.
TL;DR: These results provide the first evidence for grape leaf responses to high temperature at simultaneous transcriptional, posttranscriptional, and translational levels and indicate that AS, especially IR, is an important posttranscribedal regulatory event during grape leaf responds to highTemperature.
Abstract: Heat stress is one of the primary abiotic stresses that limit crop production. Grape (Vitis vinifera) is a cultivated fruit with high economic value throughout the world, with its growth and development often influenced by high temperature. Alternative splicing (AS) is a widespread phenomenon increasing transcriptome and proteome diversity. We conducted high-temperature treatments (35°C, 40°C, and 45°C) on grapevines and assessed transcriptomic (especially AS) and proteomic changes in leaves. We found that nearly 70% of the genes were alternatively spliced under high temperature. Intron retention (IR), exon skipping, and alternative donor/acceptor sites were markedly induced under different high temperatures. Among all differential AS events, IR was the most abundant up- and down-regulated event. Moreover, the occurrence frequency of IR events at 40°C and 45°C was far higher than at 35°C. These results indicated that AS, especially IR, is an important posttranscriptional regulatory event during grape leaf responses to high temperature. Proteomic analysis showed that protein levels of the RNA-binding proteins SR45, SR30, and SR34 and the nuclear ribonucleic protein U1A gradually rose as ambient temperature increased, which revealed a reason why AS events occurred more frequently under high temperature. After integrating transcriptomic and proteomic data, we found that heat shock proteins and some important transcription factors such as MULTIPROTEIN BRIDGING FACTOR1c and HEAT SHOCK TRANSCRIPTION FACTOR A2 were involved mainly in heat tolerance in grape through up-regulating transcriptional (especially modulated by AS) and translational levels. To our knowledge, these results provide the first evidence for grape leaf responses to high temperature at simultaneous transcriptional, posttranscriptional, and translational levels.
TL;DR: A versatile photothermal platform composed of a hollow gold nanoshell core densely packed with small interfering RNAs against heat shock protein 70 results in sensitized photothermal therapy in nude mice model under mild temperature and has great potential for clinical translation with a simple and easily controlled structure.
Abstract: The resistance of cancer cells to photothermal therapy is closely related to the overexpression of heat shock proteins (HSPs), which are abnormally upregulated when cells are under lethal stresses. Common strategies that use small molecule inhibitors against HSPs to enhance hyperthermia effect lack spatial and temporal control of drug release, leading to unavoidable systemic toxicity. Herein, a versatile photothermal platform is developed which is composed of a hollow gold nanoshell core densely packed with small interfering RNAs against heat shock protein 70 (Hsp70). Upon near infrared light irradiation, the small interfering RNAs can detach from gold surface specifically and escape from endosomes for Hsp70 silencing. Meanwhile, the temperature increases for hyperthermia therapy due to the high photothermal efficiency of the nanoshells. Efficient downregulation of Hsp70 after light activation is achieved in vitro and in vivo. Ultimately, the light-controlled dual functional nanosystem, with the effects of Hsp70 silencing and temperature elevation, results in sensitized photothermal therapy in nude mice model under mild temperature. This strategy smartly combines the localized photothermal therapy with controlled Hsp70 silencing, and has great potential for clinical translation with a simple and easily controlled structure.
TL;DR: The HSP70s belong to a small family of highly conserved ∼70 kDa enzymes that can use the energy of ATP-hydrolysis to modify the structure, and consequently the function, of specific native proteins, and to reduce the cellular concentration of harmful misfolded proteins.
Abstract: The HSP70s belong to a small family of highly conserved ∼70 kDa enzymes that can use the energy of ATP-hydrolysis to modify the structure, and consequently the function, of specific native proteins, and to unfold, solubilize, and thereby reduce the cellular concentration of harmful misfolded proteins (Finka et al., 2016). Particular HSP70s are expressed constitutively in the cytosol of bacteria and in all the ATP-containing compartments of eukaryotic cells. In unstressed bacteria, plant, and animal cells, HSP70s are 0.5–2% of the total protein mass (Finka and Goloubinoff, 2013). They form the central hub of the chaperone network that controls all aspects of cellular protein homeostasis: protein de novo synthesis, protein translocation across membranes, native folding, and oligomer assembly. HSP70s also participate in the active removal of toxic protein aggregates by actively converting them into harmless degraded peptides, or into natively refolded functional proteins (Calamini and Morimoto, 2012; Finka et al., 2016). In immortalized human cancer cells and in naïve rat livers cells for example, HSPA8 is the major HSP70 species that is constitutively expressed in the cytosol, accounting for about half of the total mass of the HSP70s (Finka and Goloubinoff, 2013). In heat-shocked cells, particular HSP70s accumulate. Hence, following a 4 h mild fever-like heat-shock at 41C, the total mass of the HSP70s in Jurkat cells increases 1.6-folds, from ∼0.7% (at 37C) to ∼1.1% (Finka et al., 2015). Thus, although sharing 90% sequence identity with HSPA8, the cytosolic HSPA1A, which generally remains undetected in unstressed tissues, strongly accumulates during various abiotic stresses (Finka et al., 2015). Noticeably, non-heat-shocked cancer cells generally express constitutively abnormally elevated levels of HSPA1A that may even exceed the naturally high amounts of HSPA8. High expression levels of HSPA1A in otherwise unstressed tissues is thus a hallmark of malignancy and of poor survival outcome (Feder et al., 1992; Finka and Goloubinoff, 2013; Yang et al., 2015). The endoplasmic reticulum HSP70, HSPA5 (called BIP), and the mitochondrial HSP70, HSPA9 (calledmortalin) are the nextmost abundant HSP70 species. As in the case of cytosolic HSPA8, their concentration may also increase in response to heat-shock (Finka et al., 2015). In addition to their function in protein quality control, they act as pulling motors that import cytosolic polypeptides into their respective organelles. Assisted by over 30 different J-domain cochaperones in eukaryotes (Dekker et al.) and various nucleotide exchange factors (NEFs) (Bracher and Verghese), the HSP70s can control a great number of housekeeping cellular processes. They can use the energy of ATP-hydrolysis to convert active (alter)native protein complexes into differently active native polypeptides. Thus,
TL;DR: Novel and effective interventions through HSP inhibition are expected to decrease the burden of cancer in the near future and more experimental studies are required to elucidate the reliability and efficacy of heat shock proteins in combination with other conventional markers for cancer diagnosis and prognosis.
Abstract: Background Heat Shock Proteins (HSPs) constitute a group of proteins that play a crucial role in the process of protein folding. HSPs are also known to modulate a number of key apoptotic factors. High expression of these proteins is reported in an array of cancers, such as breast, prostate, colorectal, lung, ovarian, gastric, oral and esophageal cancer. Ample amount of investigations were carried out on a variety of cancers suggesting HSPs as a promising hallmark in cancers. Their expression profile in several tumors elucidates that they help in proliferation, invasion, metastasis and death of cancerous cells. Detection of the levels of heat shock proteins and their specific antibodies in the sera of diseased individuals can play an important role in cancer diagnosis. Objectives This review will present and summarize latest research being carried out on heat shock proteins. It will also highlight the clinical and prognostic features of HSP27, HSP60, HSP70, HSP90 and HSP110, and will discuss future implications of HSPs in the diagnosis and prognosis of cancer. Furthermore, the role of heat shock proteins as a therapeutic target in cancer will be discussed. In addition, the review article will report various studies, where HSPs have been targeted for their therapeutic potential. Conclusion In summary, multiple experimental investigations have been successful in suggesting the role of heat shock protein as a clinical biomarker and therapeutic target in cancer. HSPs are associated with a number of cancer hallmarks such as cell proliferation, invasion and metastasis. Inhibition of HSPs has resulted in successful therapeutic outcome in cancer. It has served as a novel anti-cancer therapy for the treatment of several cancer forms. However, more experimental studies are required to elucidate the reliability and efficacy of heat shock proteins in combination with other conventional markers for cancer diagnosis and prognosis. Novel and effective interventions through HSP inhibition are expected to decrease the burden of cancer in the near future.
TL;DR: It is revealed that piR‐823 plays a tumor‐promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR-823 as a potential therapeutic target for CRC.
Abstract: Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, were first discovered in germline cells and are thought to silence transposons in spermatogenesis. Recently, piRNAs have also been identified in somatic tissues, and aberrant expression of piRNAs in tumor tissues may be implicated in carcinogenesis. However, the function of piR-823 in colorectal cancer (CRC) remains unclear. Here, we first found that piR-823 was significantly upregulated in CRC tissues compared with its expression in the adjacent tissues. Inhibition of piR-823 suppressed cell proliferation, arrested the cell cycle in the G1 phase and induced cell apoptosis in CRC cell lines HCT116 and DLD-1, whereas overexpression of piR-823 promoted cell proliferation in normal colonic epithelial cell line FHC. Interestingly, Inhibition of piR-823 repressed the expression of heat shock protein (HSP) 27, 60, 70. Furthermore, elevated HSPs expression partially abolished the effect of piR-823 on cell proliferation and apoptosis. In addition, we further demonstrated that piR-823 increased the transcriptional activity of HSF1, the common transcription factor of HSPs, by binding to HSF1 and promoting its phosphorylation at Ser326. Our study reveals that piR-823 plays a tumor-promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR-823 as a potential therapeutic target for CRC.
TL;DR: The results illustrate the complexity of the TaHSP20 gene family and its stress regulation in wheat, and suggest that sHSPs as attractive breeding targets for improvement of the heat tolerance of wheat.
TL;DR: In this article, the effects of HSP90 inhibitors on cells with disruption of the microRNA 21 (MIR21 or miRNA21) gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of microRNA21 were investigated.
TL;DR: Results suggested that sub-chronic exposure to arsenic induced neurotoxicity in chickens, which disturbed the balance of oxidants and antioxidants, and increased heat shock response tried to protect chicken brain tissues from tissues damage caused by oxidative stress.
TL;DR: It is shown that LIN treatment rapidly increases the levels of aggregated proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones, and folding capacity is increased to restore protein homeostasis.
Abstract: Disruption of protein homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme. The repair pathway is promoted when the levels of ClpB3 proteins increase upon reduction of Clp protease activity in mutants or wild-type plants treated with the chloroplast protein synthesis inhibitor lincomycin (LIN). Here we show that LIN treatment rapidly increases the levels of aggregated proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones. As a consequence, folding capacity is increased to restore protein homeostasis. This sort of chloroplast unfolded protein response (cpUPR) mechanism appears to be mediated by the heat shock transcription factor HsfA2. Expression of HsfA2 and cpUPR-related target genes is independent of GUN1, a central integrator of retrograde signaling pathways. However, double mutants defective in both GUN1 and plastome gene expression (or Clp protease activity) are seedling lethal, confirming that the GUN1 protein is essential for protein homeostasis in chloroplasts.
TL;DR: The present review is an attempt to signify the importance of heat shock proteins in livestock adaptation during heat stress, and HSP70 was identified to be the ideal biological marker for quantifying heat stress in animals.
Abstract: The present review is an attempt to signify the importance of heat shock proteins in livestock adaptation during heat stress. The cellular and molecular responses in livestock are very crucial as it may lead to identification of confirmatory biomarker for heat stress in livestock. Thermo-tolerant gene expression and elevated heat shock protein (HSP) levels are observed to be the ultimate response through which the cell survives the heat stress. The HSPs have chaperonic activity ensuring the folding, unfolding and refolding of stress-denatured proteins. The components of heat shock response include heat shock factors (HSFs), heat shock element (HSE) and HSP. The cellular response to heat stress in mammalian organisms is controlled at the transcription level and it is mediated by a family of HSF which are regulated by the corresponding HSF genes. The activated HSFs bind with the HSE in the promoter region of HSP genes culminating in enhanced transcription of HSP mRNA. The HSP70, HSP90 and HSP27 are the predominant HSPs having protective role during heat stress in farm animals. Among these HSPs studied, HSP70 was identified to be the ideal biological marker for quantifying heat stress in animals.
TL;DR: The molecular mechanism of heat shock protein 70 kDa (Hsp70) action and its structural and functional analysis, research progress on the interaction of Hsp70 with other proteins and their interaction mechanisms as well as the involvement of HSp70 in abiotic stress responses as an adaptive defense mechanism are reported.
Abstract: Studying the strategies of improving abiotic stress tolerance is quite imperative and research under this field will increase our understanding of response mechanisms to abiotic stress such as heat. The Hsp70 is an essential regulator of protein having the tendency to maintain internal cell stability like proper folding protein and breakdown of unfolded proteins. Hsp70 holds together protein substrates to help in movement, regulation, and prevent aggregation under physical and or chemical pressure. However, this review reports the molecular mechanism of heat shock protein 70 kDa (Hsp70) action and its structural and functional analysis, research progress on the interaction of Hsp70 with other proteins and their interaction mechanisms as well as the involvement of Hsp70 in abiotic stress responses as an adaptive defense mechanism.
TL;DR: A comprehensive vision of the very complex scenario in which IDE takes part is addressed, outlining its crucial role in interconnecting several relevant cellular processes, suggesting a major implication in proteins turnover and cell homeostasis.
Abstract: Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involve...
TL;DR: A novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles is revealed, leading to severely compromised cardiac function during cardiac hypertrophy.
Abstract: Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.
TL;DR: The results of this study provide a comprehensive overview of heat stress-induced transcriptional patterns in rainbow trout liver and would be particularly useful for further studies on the molecular mechanisms underlying responses to heat stress in this species.
TL;DR: Current understanding of HSP bioactivity in the pathophysiology of various kidney diseases, including acute kidney injury, diabetic nephropathy, chronic glomerulonephritis, and lupus nephritis is summarized—along with other promising strategies for their remediation, such as DNA vaccination.
Abstract: Heat shock proteins (HSPs) mediate a diverse range of cellular functions, prominently including folding and regulatory processes of cellular repair. A major property of these remarkable proteins, dependent on intracellular or extracellular location, is their capacity for immunoregulation that optimizes immune activity while avoiding hyperactivated inflammation. In this review, recent investigations are described, which examine roles of HSPs in protection of kidney tissue from various traumatic influences and demonstrate their potential for clinical management of nephritic disease. The HSP70 class is particularly attractive in this respect due to its multiple protective effects. The review also summarizes current understanding of HSP bioactivity in the pathophysiology of various kidney diseases, including acute kidney injury, diabetic nephropathy, chronic glomerulonephritis, and lupus nephritis-along with other promising strategies for their remediation, such as DNA vaccination.
TL;DR: The SIRT1/heat shock factor 1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced ER stress and hepatic steatosis, which provides evidence for a molecular mechanism to support exen atide and incretin mimetics as promising therapeutics for obesity‐induced hepatic Steatosis.
TL;DR: It is proposed that, after HS, HSP101 is required for the efficient release of RP mRNAs from SGs resulting in a rapid restoration of the translation machinery by producing new RPs.
Abstract: Heat shock (HS) is known to have a profound impact on gene expression at different levels, such as inhibition of protein synthesis, in which HS blocks translation initiation and induces the sequestration of mRNAs into stress granules (SGs) or P-bodies for storage and/or decay. SGs prevent the degradation of the stored mRNAs, which can be reengaged into translation in the recovery period. However, little is known on the mRNAs stored during the stress, how these mRNAs are released from SGs afterward, and what the functional importance is of this process. In this work, we report that Arabidopsis HEAT SHOCK PROTEIN101 (HSP101) knockout mutant (hsp101) presented a defect in translation recovery and SG dissociation after HS Using RNA sequencing and RNA immunoprecipitation approaches, we show that mRNAs encoding ribosomal proteins (RPs) were preferentially stored during HS and that these mRNAs were released and translated in an HSP101-dependent manner during recovery. By 15N incorporation and polysome profile analyses, we observed that these released mRNAs contributed to the production of new ribosomes to enhance translation. We propose that, after HS, HSP101 is required for the efficient release of RP mRNAs from SGs resulting in a rapid restoration of the translation machinery by producing new RPs.
TL;DR: A model for early transcriptional regulation of protein degradation and cell adhesion response that may ultimately lead to the bleaching and stress response is proposed.
Abstract: Corals respond to heat pulses that cause bleaching with massive transcriptional change, but the immediate responses to stress that lead up to these shifts have never been detailed Understanding these early signals could be important for identifying the regulatory mechanisms responsible for bleaching and how these mechanisms vary between more and less resilient corals Using RNA sequencing (RNAseq) and sampling every 30 minutes during a short-term heat shock, we found that components of the transcriptome were significantly upregulated within 90 min and after a temperature increase of +2 °C The developmental transcription factor, Kruppel-like factor 7, was highly expressed within 60 min, and stress-related transcription factors such as Elk-3 were highly expressed starting at 240 min The sets of genes enriched for early transcriptional response to heat stress included heat shock proteins, small GTPases, and proteasome genes Retrovirus-related Pol polyproteins from transposons were significantly expressed throughout the whole experiment Lastly, we propose a model for early transcriptional regulation of protein degradation and cell adhesion response that may ultimately lead to the bleaching and stress response
TL;DR: It is demonstrated that ablation of FABP4/aP2 regulates systemic redox capacity and reduces cellular protein sulfhydryl oxidation and, in particular, oxidation of mitochondrial protein cysteine residues.
Abstract: Obesity-linked metabolic disease is mechanistically associated with the accumulation of proinflammatory macrophages in adipose tissue, leading to increased reactive oxygen species (ROS) production and chronic low-grade inflammation. Previous work has demonstrated that deletion of the adipocyte fatty acid-binding protein (FABP4/aP2) uncouples obesity from inflammation via upregulation of the uncoupling protein 2 (UCP2). Here, we demonstrate that ablation of FABP4/aP2 regulates systemic redox capacity and reduces cellular protein sulfhydryl oxidation and, in particular, oxidation of mitochondrial protein cysteine residues. Coincident with the loss of FABP4/aP2 is the upregulation of the antioxidants superoxide dismutase (SOD2), catalase, methionine sulfoxide reductase A, and the 20S proteasome subunits PSMB5 and αβ. Reduced mitochondrial protein oxidation in FABP4/aP2-/- macrophages attenuates the mitochondrial unfolded-protein response (mtUPR) as measured by expression of heat shock protein 60, Clp protease, and Lon peptidase 1. Consistent with a diminished mtUPR, FABP4/aP2-/- macrophages exhibit reduced expression of cleaved caspase-1 and NLRP3. Secretion of interleukin 1β (IL-1β), in response to inflammasome activation, is ablated in FABP4/aP2-/- macrophages, as well as in FABP4/aP2 inhibitor-treated cells, but partially rescued in FABP4/aP2-null macrophages when UCP2 is silenced. Collectively, these data offer a novel pathway whereby FABP4/aP2 regulates macrophage redox signaling and inflammasome activation via control of UCP2 expression.