heat shock protein
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Heat shock proteins (HSP) are a family of
proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a Nobe ...

proteins
that are produced by
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
in response to exposure to stressful conditions. They were first described in relation to
heat shockThe heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal ...
, 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 In the biological context of organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties of life. It is a synonym for "Ou ...
of the heat shock proteins is a key part of the
heat shock responseThe heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal c ...
and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from
bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the sm ...

bacteria
to
human Humans (''Homo sapiens'') are the most abundant and widespread species In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...

human
s. Heat-shock proteins are named according to their molecular weight. For example,
Hsp60 HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 belo ...
,
Hsp70#REDIRECT Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other r ...

Hsp70
and
Hsp90#REDIRECT hsp90 of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, p ...

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 Ubiquitin is a small (8.6 kDa The dalton or unified atomic mass unit (symbols: Da or u) is a unit of mass widely used in physics and chemistry. It is defined as 1/12 of the mass of an unbound neutral atom of carbon-12 in its nuclear and elec ...
, 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 Ferruccio Ritossa (February 26, 1936 – January 9, 2014) was an Italian geneticist best known for his discovery of the heat shock response in the model organism ''Drosophila'' (fruit flies). Early life and education Ritossa was born in the town ...
reported that heat and the metabolic uncoupler 2,4-Dinitrophenol, 2,4-dinitrophenol induced a characteristic pattern of "chromosome puff, 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 chaperone (protein), chaperons in the refolding of proteins damaged by heat stress. Heat shock proteins have been found in all species examined, from
bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the sm ...

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 (biology), 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 (medical), 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 In the biological context of organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties of life. It is a synonym for "Ou ...
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, Repression of heat shock gene expression (ROSE) element, ROSE element and the Hsp90 cis-regulatory element. Petersen and Mitchell found that in ''Drosophila melanogaster, 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 (biology), translation of messenger RNA rather than transcription (biology), 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 Chemical conformation, 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 Proteolysis, 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#REDIRECT hsp90 of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, p ...

Hsp90
binds both Endothelial NOS, endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation. 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, HSP90B1, 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 Toll-like receptor, 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.


Function in 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 Endoplasmic reticulum, ER through protein transporter Transporter associated with antigen processing, TAP and loaded onto MHC class I, 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 MHC class I, MHCI.
Hsp90#REDIRECT hsp90 of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, p ...

Hsp90
can associate with proteasome and take over generated peptides. Afterwards, it can associate with hsp70, which can take the peptide further to the Transporter associated with antigen processing, TAP. After passing through TAP, an ER chaperons are getting important - calreticulin binds peptides and together with HSP90B1, 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 Receptor-mediated endocytosis, 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 receptor (immunology), 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, hsp60 and hsp70. SRECI is now considered to by the common heat-shock protein receptor because it binds HSP60, hsp60, hsp70, hsp90, hsp110, HSP90B1, gp96 and GRP170. The relevance for this type of cross-presentation is high especially in Cancer immunology, 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.


Heat-shock proteins as 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 cell, antigen presenting cells by upregulation of Co-stimulation, co-stimulation molecules (CD80, CD86, CD40), Major histocompatibility complex, MHC molecules and pro-inflammatory and Th1 cytokines. Heat-shock proteins can signal also through Scavenger receptor (immunology), scavenger receptors, which can either associate with TLRs, or activate pro-inflammatory intracelular pathways like MAPK or NF-κB, NF-kB. With the exception of SRA, which down-regulates immune response.


How heat-shock proteins get 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 Interleukin 1 beta, IL1b, and it is induced by stress conditions. Another possibility is release of HSPs during cell necrosis, or secretion of HSPs in Exosome (vesicle), exosomes. During special types of Apoptosis, apoptotic cell death (for example induced by some Chemotherapy, 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 immune system or suppress immunity. They can promote T helper 17 cell, Th17, Th1 cell, Th1, Th2 or Treg responses depending on antigen-presenting cells. As a result, the clinical use of heat-shock proteins is both in cancer treatment (boosting an immune response) and treatment of autoimmune diseases (suppress of immunity).


Lens

Alpha crystallin (Α-crystallin, α4- crystallin) or hspb4 is involved in the development of lens in Zebrafish as it is expressed in response to heat shock in the Zebrafish embryo in its developmental stages.


Clinical significance

HSF1, Heat shock factor 1 (HSF1) is a transcription factor that is involved in the general maintenance and upregulation of Hsp70 protein expression. Recently it was discovered that HSF1 is a powerful multifaceted modifier of carcinogenesis. HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of 7,12-dimethylbenz(a)anthracene, DMBA (7,12-dimethylbenzanthracene), a mutagen. Moreover, HSF1 inhibition by a potent RNA aptamer attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.


Applications


Cancer vaccines

Given their role in presentation, HSPs are useful as immunologic adjuvants (DAMPS) in boosting the response to a vaccine. Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system. Therefore, HSPs may be useful for increasing the effectiveness of cancer vaccines. Also isolated HSPs from tumour cells are able to act as a specific anti-tumour vaccine by themselves. Tumour cells express a lot of HSPs because they need to chaperone mutated and over-expressed oncogenes, tumour cells are also in a permanent stress. When we isolate HSPs from a tumour, the peptide repertoire bound by HSPs is somewhat a fingerprint of these particular tumour cells. Application of such HSPs back into patient then stimulate immune system (promotes efficient antigen presentation and act as DAMP) specifically against the tumour and leads to tumour regression. This Immunization, immunisation is not functional against a different tumour. It was used in autologous manner in clinical studies for gp96 and hsp70, but in vitro this works for all immune-relevant HSPs.


Anticancer therapeutics

Intracellular heat shock proteins are highly expressed in cancerous cells and are essential to the survival of these cell types due to presence of mutated and over-expressed oncogenes. Many HSPs can also promote invasiveness and metastasis formation in tumours, block apoptosis, or promote resistance to anti-cancer drugs. Hence small molecule HSP inhibitor, inhibitors of HSPs, especially
Hsp90#REDIRECT hsp90 of the ATP binding pocket of Hsp90 where ATP is represented by a ball and stick figure (carbon atoms = grey, nitrogen = blue, oxygen = red, phosphorus = orange) and Hsp90 is depicted as a solid surface (negatively charged = red, p ...

Hsp90
show promise as anticancer agents. The potent Hsp90 inhibitor 17-N-Allylamino-17-demethoxygeldanamycin, 17-AAG was in clinical trials for the treatment of several types of cancer, but for various reasons unrelated to efficacy did not go on to Phase 3. HSPgp96 also shows promise as an anticancer treatment and is currently in clinical trials against non-small cell lung cancer.


Autoimmunity treatment

Acting as Damage-associated molecular pattern, DAMPs, HSPs can extracellularly promote Autoimmune disease, autoimmune reactions leading to diseases as rheumatoid arthritis or systemic lupus erythematosus. Nevertheless, it was found, that application of some HSPs into patients is able to induce immune tolerance and treat autoimmune diseases. The underlying mechanism is not known. HSPs (especially hsp60 and hsp70) are used in clinical studies to treat rheumatoid arthritis and Diabetes mellitus type 1, type I. diabetes. Hsp90 inhibitors are another possible treatment for autoimmunity, because hsp90 is necessary for proper folding of many pro-inflammatory proteins (components of PI3K/AKT/mTOR pathway, PI3K, MAPK/ERK pathway, MAPK and NF-κB, NF-kB cascades).


Agricultural

Researchers are also investigating the role of HSPs in conferring stress tolerance to hybridized plants, hoping to address drought and poor soil conditions for farming. Various HSPs were shown to be differentially expressed in the leaf and root of drought-tolerant and drought-sensitive sorghum varieties in response to drought.


Classification

The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33, HSP60, hsp70, HSP70/HSP110, hsp90, HSP90, HSP100, and the small heat-shock proteins (sHSPs). A standard nomenclature for human HSP genes is available. Although the most important members of each family are tabulated here, some species may express additional chaperones, co-chaperones, and heat shock proteins not listed. In addition, many of these proteins may have multiple splicing (genetics), splice variants (Hsp90α and Hsp90β, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70).


See also

* Cellular Stress Response, Cellular stress response * Chaperone (protein), Chaperone * Chaperonin * Co-chaperone * FourU thermometer * Hsp90 cis-regulatory element * Repression of heat shock gene expression (ROSE) element, ROSE element * HSF1


References


External links

* {{DEFAULTSORT:Heat Shock Protein Heat shock proteins,