heat shock protein heat shock protein heat shock proteins (hsp) are a family of proteins produced by cells in response to exposure to stressful conditions. they were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, uv light and during wound healing or tissue remodeling. many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. this increase in expression is transcriptionally regulated. the dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (hsf). hsps are found in virtually all living organisms, from bacteria to humans. heat-shock proteins are named according to their molecular weight. for example, hsp60, hsp70 and hsp90 (the most widely studied hsps) refer to families of heat shock proteins on the order of 60, 70 and 90 kilodaltons in size, respectively. the small 8-kilodalton protein ubiquitin, which marks proteins for degradation, also has features of a heat shock protein. a conserved protein binding domain of approximately 80 amino-acid alpha crystallins are known as small heat shock proteins (shsp). discovery it is known that rapid heat hardening can be elicited by a brief exposure of cells to sub-lethal high temperature, which in turn provides protection from subsequent and more severe temperature. in 1962, italian geneticist ferruccio ritossa reported that heat and the metabolic uncoupler 2,4-dinitrophenol induced a characteristic pattern of "puffing" in the chromosomes of drosophila. this discovery eventually led to the identification of the heat-shock proteins (hsp) or stress proteins whose expression this puffing represented. increased synthesis of selected proteins in drosophila cells following stresses such as heat shock was first reported in 1974. in 1974, tissieres, mitchell and tracy discovered that heat-shock induces the production of a small number of proteins and inhibits the production of most others. this initial biochemical finding gave rise to a large number of studies on the induction of heat shock and its biological role. heat shock proteins often function as chaperons in the refolding of proteins damaged by heat stress. heat shock proteins have been found in all species examined, from bacteria to humans, suggesting that they evolved very early and have an important function. function according to marvin et al. shsps independently express not only in heat shock response but also have developmental roles in embryonic or juvenile stages of mammals, teleost fish and some lower vertebral genomes. hspb1 (hsp27) is expressed during stress and during the development of embryo, somites, mid-hindbrain, heart and lens in zebrafish. expression of the hspb4 gene, which codes for alpha crystallin, increases considerably in the lens in response to heat shock. upregulation in stress production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to harmful materials (ethanol, arsenic, and trace metals, among many others), ultraviolet light, starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants) or water deprivation. as a consequence, the heat shock proteins are also referred to as stress proteins and their upregulation is sometimes described more generally as part of the stress response. the mechanism by which heat-shock (or other environmental stressors) activates the heat shock factor has been determined in bacteria. during heat stress, outer membrane proteins (omps) do not fold and cannot insert correctly into the outer membrane. they accumulate in the periplasmic space. these omps are detected by degs, an inner membrane protease, that passes the signal through the membrane to the sigmae transcription factor. however, some studies suggest that an increase in damaged or abnormal proteins brings hsps into action. some bacterial heat shock proteins are upregulated via a mechanism involving rna thermometers such as the fouru thermometer, rose element and the hsp90 cis-regulatory element. petersen and mitchell found that in d. melanogaster a mild heat shock pretreatment which induces heat shock gene expression (and greatly enhances survival after a subsequent higher temperature heat shock) primarily affects translation of messenger rna rather than transcription of rna. heat shock proteins are also synthesized in d. melanogaster during recovery from prolonged exposure to cold in the absence of heat shock. a mild heat shock pretreatment of the same kind that protects against death from subsequent heat shock also prevents death from exposure to cold. role as chaperone several heat shock proteins function as intra-cellular chaperones for other proteins. they play an important role in protein–protein interactions such as folding and assisting in the establishment of proper protein conformation (shape) and prevention of unwanted protein aggregation. by helping to stabilize partially unfolded proteins, hsps aid in transporting proteins across membranes within the cell. some members of the hsp family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance. management heat-shock proteins also occur under non-stressful conditions, simply "monitoring" the cell's proteins. some examples of their role as "monitors" are that they carry old proteins to the cell's "recycling bin" (proteasome) and they help newly synthesised proteins fold properly. these activities are part of a cell's own repair system, called the "cellular stress response" or the "heat-shock response". recently, there are several studies that suggest a correlation between hsps and dual frequency ultrasound as demonstrated by the use of ldm-med machine. heat shock proteins appear to be more susceptible to self-degradation than other proteins due to slow proteolytic action on themselves. cardiovascular heat shock proteins appear to serve a significant cardiovascular role. hsp90, hsp84, hsp70, hsp27, hsp20, and alpha b crystallin all have been reported as having roles in the cardiovasculature. hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation. the subset of hsp70, extracellular hsp70 (ehsp70) and intracellular hsp70 (ihsp70), has been shown to have a pivotal role in managing oxidative stress and other physiological factors. krief et al. referred hspb7 (cvhsp - cardiovascular heat shock protein) as cardiac heat shock protein. gata4 is an essential gene responsible for cardiac morphogenesis. it also regulates the gene expression of hspb7 and hspb12. gata4 depletion can result in reduced transcript levels of hspb7 and hspb12 and this could result in cardiac myopathies in zebrafish embryos as observed by gabriel et al. hspb7 also acts in the downregulation of kupffer vesicles which is responsible for regulation of left-right asymmetry of heart in zebrafish. along with hspb7, hspb12 is involved in cardiac laterality determination. a kinase of the nitric oxide cell signalling pathway, protein kinase g, phosphorylates a small heat shock protein, hsp20. hsp20 phosphorylation correlates well with smooth muscle relaxation and is one significant phosphoprotein involved in the process. hsp20 appears significant in development of the smooth muscle phenotype during development. hsp20 also serves a significant role in preventing platelet aggregation, cardiac myocyte function and prevention of apoptosis after ischemic injury, and skeletal muscle function and muscle insulin response. hsp27 is a major phosphoprotein during women's contractions. hsp27 functions in small muscle migrations and appears to serve an integral role. immunity function of heat-shock proteins in immunity is based on their ability to bind not only whole proteins, but also peptides. the affinity and specificity of this interaction is typically low. it was shown, that at least some of the hsps possess this ability, mainly hsp70, hsp90, gp96 and calreticulin, and their peptide-binding sites were identified. in the case of gp96 it is not clear whether it can bind peptides in vivo, although its peptide-binding site has been found. but gp96 immune function could be peptide-independent, because it is involved in proper folding of many immune receptors, like tlr or integrins. apart from that, hsps can stimulate immune receptors and are important in proper folding of proteins involved in pro-inflammatory signaling pathways. antigen presentation hsps are indispensable components of antigen presentation pathways - the classical ones and also cross-presentation and autophagy. mhci presentation in the simplified view of this pathway hsps are usually not mentioned: antigenic peptides are generated in proteasome, transported into er through protein transporter tap and loaded onto mhci, which then goes through secretory pathway on plasma membrane. but hsps play an important part in transfer of unfolded proteins to proteasome and generated peptides to mhci. hsp90 can associate with proteasome and take over generated peptides. afterwards, it can associate with hsp70, which can take the peptide further to the tap. after passing through tap, an er chaperons are getting important - calreticulin binds peptides and together with gp96 form peptide loading complex for mhci. this handing over with peptides is important, because hsps can shield hydrophobic residues in peptides which would be otherwise problematic in aquatic cytosol. also simple diffusion of peptides would be too ineffective. mhcii presentation in mhcii presentation, hsps are involved in clathrin-dependent endocytosis. also when hsps are extracellular, they can guide their associated peptides into mhcii pathway, although it is not known how they are distinguished from the cross-presented ones (see below). autophagy hsps are involved in classical macroautophagy, when protein aggregates are enclosed by double membrane and degraded afterwards. they are also involved in special type of autophagy called "chaperone-mediated autophagy", when they enable cytosolic proteins to get into lysosomes. cross-presentation when hsps are extracellular, they can bind to specific receptors on dendritic cells (dc) and promote cross-presentation of their carried peptides. the most important receptors in this case are scavenger receptors, mainly sreci and lox-1. cd91 scavenger receptor has been previously proposed as the common hsp receptor. but now its relevance is controversial because the majority of dc types does not express cd91 in relevant amounts and the binding capacity for many hsps has not been proved. stimulation of some scavenger receptors can even result in immunosuppression, this is the case for sra. lox-1 and sreci when stimulated guide hsps with their associated peptides into cross-presentation. lox-1 binds mainly hsp60 and hsp70. sreci is now considered to by the common heat-shock protein receptor because it binds hsp60, hsp70, hsp90, hsp110, gp96 and grp170. the relevance for this type of cross-presentation is high especially in tumour-immunosurveillance. thanks to the hsp, the bound peptide is protected against degradation in dendritic cell compartments and the efficiency of cross-presentation is higher. also internalisation of hsp-peptide complex is more efficient than internalisation of soluble antigens. tumor cells usually express only a few neo-antigens, which can be targeted by immune system and also not all tumor cells express them. because of that the amount of tumor antigens is restricted and high efficiency of cross-presentation is necessary for mounting strong immune response. hsp70 and hsp90 are also involved intracellulary in cytosolic pathway of cross-presentation where they help antigens to get from endosome into the cytosol. damage-associated molecular patterns extracellular heat-shock proteins can be sensed by the immunity as damage-associated molecular patterns (damps). they are able to interact with pattern recognition receptors like tlr2 or tlr4 and activate antigen presenting cells by upregulation of co-stimulation molecules (cd80, cd86, cd40), mhc molecules and pro-inflammatory and th1 cytokines. hsp70 was shown to react to damp release, causing an influx of hsp70-positive t-evs (tumor cells) that initiate anti-tumor immune signaling cascades. heat-shock proteins can signal also through scavenger receptors, which can either associate with tlrs, or activate pro-inflammatory intracellular pathways like mapk or nf-kb. with the exception of sra, which down-regulates immune response. transport into extracellular space heat-shock proteins can be secreted from immune cells or tumour cells by non-canonical secretion pathway, or leaderless pathway, because they do not have the leader peptide, which navigate proteins into endoplasmic reticulum. the non-canonical secretion can be similar to the one, which occurs for il1b, and it is induced by stress conditions. another possibility is release of hsps during cell necrosis, or secretion of hsps in exosomes. during special types of apoptotic cell death (for example induced by some chemotherapeutics), hsps can also appear on the extracellular side of plasma membrane. there is a debate about how long can hsp keep its peptide in extracellular space, at least for hsp70 the complex with peptide is quite stable. the role of extracellular hsps can be miscellaneous. it depends a lot on context of tissue whether hsps will stimulate the