Heat shock proteins (HSP) are a family of
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s produced by
cells in response to exposure to
stressful conditions. They were first described in relation to
heat shock
The 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 organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
of the heat shock proteins is a key part of the
heat shock response and is induced primarily by
heat shock factor
In molecular biology, heat shock factors (HSF), are the transcription factors that regulate the expression of the heat shock proteins. A typical example is the heat shock factor of ''Drosophila melanogaster''.
Function
Heat shock factors (H ...
(HSF).
HSPs are found in virtually all living organisms, from
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
to
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
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 bel ...
,
Hsp70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
and
Hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
(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) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
, 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 t ...
reported that heat and the metabolic uncoupler
2,4-dinitrophenol
2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimates, is volatile with steam, and is soluble in most organic solvents as well ...
induced a characteristic pattern of "
puffing" in the
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
s of
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
.
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
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
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
In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast c ...
, 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
Stress may refer to:
Science and medicine
* Stress (biology), an organism's response to a stressor such as an environmental condition
* Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
conditions, such as
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
,
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
, exercise, exposure of the cell to harmful materials (
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
,
arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, ...
, and
trace metals, among many others),
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
light,
starvation,
hypoxia (
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
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 organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
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
The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the ''periplasmic space'' in gram-negative bacteria. Using cryo-electron microscopy it has been found tha ...
. These OMPs are detected by DegS, an inner membrane
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
, 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
__NOTOC__
FourU thermometers are a class of non-coding RNA thermometers found in ''Salmonella''. They are named 'FourU' due to the four highly conserved uridine nucleotides found directly opposite the Shine-Dalgarno sequence on hairpin II (''pict ...
,
ROSE element and the
Hsp90 cis-regulatory element
The Hsp90 cis regulatory element is an RNA element (RNA thermometer) found in the 5' UTR of the ''Drosophila'' hsp90 mRNA. It is required for increased translation
Translation is the communication of the meaning of a source-language t ...
.
Petersen and Mitchell
found that in ''
D. melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'' 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
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
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
Heat shock protein 27 (Hsp27) also known as heat shock protein beta-1 (HSPB1) is a protein that in humans is encoded by the ''HSPB1'' gene.
Hsp27 is a chaperone of the sHsp (small heat shock protein) group among α-crystallin, Hsp20, and others. ...
, hsp20
The heat shock protein Hsp20 family, also known as small heat shock proteins (sHSPs), is a family of heat shock proteins.
Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of protei ...
, and alpha B crystallin
Alpha-crystallin B chain is a protein that in humans is encoded by the ''CRYAB'' gene. It is part of the small heat shock protein family and functions as molecular chaperone that primarily binds misfolded proteins to prevent protein aggregation, a ...
all have been reported as having roles in the cardiovasculature.
Hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
binds both endothelial nitric oxide synthase
Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the ''NOS3'' gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms tha ...
and soluble guanylate cyclase
Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
, 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
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
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
cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle ...
, 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
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
, hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
, gp96
Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the ''HSP90B1'' gene.
HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum. ...
and calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the ''CALR'' gene.
Calreticulin is a multifunctional soluble prote ...
, 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 integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
s.
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
Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, n ...
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 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...
on plasma membrane.
But HSPs play an important part in transfer of unfolded proteins to proteasome and generated peptides to MHCI. Hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
can associate with proteasome and take over generated peptides. Afterwards, it can associate with hsp70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
, which can take the peptide further to the TAP. After passing through TAP, an ER chaperons are getting important - calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the ''CALR'' gene.
Calreticulin is a multifunctional soluble prote ...
binds peptides and together with gp96
Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the ''HSP90B1'' gene.
HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum. ...
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
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 bel ...
and hsp70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
. SRECI is now considered to by the common heat-shock protein receptor because it binds 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 bel ...
, hsp70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
, hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
, hsp110, gp96
Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the ''HSP90B1'' gene.
HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum. ...
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 pattern
Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated ...
s (DAMPs). They are able to interact with pattern recognition receptor
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
s like TLR2 or TLR4 and activate antigen presenting cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
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
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
(for example induced by some chemotherapeutics
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
), 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 Th17
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...
, Th1, Th2 or Treg
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosu ...
responses depending on antigen-presenting cells.
As a result, the clinical use of heat-shock proteins is both in cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
treatment (boosting an immune response) and treatment of autoimmune diseases (suppress of immunity).
Lens
Alpha 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
HSF-1
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
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
. HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of DMBA (7,12-dimethylbenzanthracene), a mutagen. Moreover, HSF1 inhibition by a potent RNA aptamer
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities ( KD in the pM to μM range), with little or no off-target bindin ...
attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.
Diabetes mellitus
Diabetes Mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
(DM) is a immune-disease characterized by the presence of hyperglycemia. Typically these symptoms are brought about by insulin deficiency. However, there have been many recent articles alluding to a correlation between hsp70, in some cases hsp60, and DM. Another recent article discovered the ratio of ehsp70 and ihsp70 could have an effect on DM, leading to a sufficient biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
. Serum levels of hsp70 have also been shown to increase over time in patients with hsp70, which is indicative of insulin deficiency.
Cancer
Heat Shock Protein expression plays a pivotal role in cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
identification. Recent discoveries have shown that high concentrations of eHSP can indicate the presence of contentious tumors. Additionally, HSPs have been shown to benefit oncologist in oral cancer diagnosis. Using techniques such as dot immunoassay
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
and ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presen ...
test researchers have been able to determine that HSP-specific phage antibodies could be beneficial ''in-vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology and ...
'' cancer diagnosis markers. HSPs have also been shown to interact with cancer adaptations such as drug resistance, tumor cell production and lifespan, and the up-regulation and down-regulation of oncomirs.
Applications
Cancer vaccines
Given their role in presentation
A presentation conveys information from a speaker to an audience. Presentations are typically demonstrations, introduction, lecture, or speech meant to inform, persuade, inspire, motivate, build goodwill, or present a new idea/product. Presenta ...
, HSPs are useful as immunologic adjuvant
In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word ''adiuvare'', meaning to help or aid. "An immunologic adjuvant is defined as any substance that ...
s (DAMPS) in boosting the response to a vaccine
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. . Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system. In a recent study published by Sedlacek et al., HSP was shown to effect different signaling pathways involved in carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
responses such as STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family.
Function
All STAT molecules are phosphorylated by receptor associ ...
activation, gp96-activated macrophages, and activation of NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
. Therefore, HSPs may be useful for increasing the effectiveness of cancer vaccines.
Also isolated HSPs from tumor cells are able to act as a specific anti-tumor vaccine by themselves. Tumour cells express a lot of HSPs because they need to chaperone mutated and over-expressed oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s, 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 tumor and leads to tumor regression. This immunisation
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the immunogen).
When this system is exposed to molecules that are foreign to the body, called ''non-se ...
is not functional against a different tumour. It was used in autologous
Autotransplantation is the transplantation of organs, tissues, or even particular proteins from one part of the body to another in the same person ('' auto-'' meaning "self" in Greek).
The autologous tissue (also called autogenous, autogenei ...
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
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...
inhibitors of HSPs, especially Hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
show promise as anticancer agents. The potent Hsp90 inhibitor 17-AAG
Tanespimycin (17-''N''-allylamino-17-demethoxygeldanamycin, 17-AAG) is a derivative of the antibiotic geldanamycin that is being studied in the treatment of cancer, specifically in younger patients with certain types of leukemia or solid tumors, e ...
was in clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s 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 DAMPs
Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated ...
, HSPs can extracellularly promote autoimmune reactions leading to diseases as rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
or systemic lupus erythematosus. Nevertheless, it was found, that application of some HSPs into patients is able to induce immune tolerance
Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...
and treat autoimmune diseases. The underlying mechanism is not known. HSPs (especially hsp60 and hsp70) are used in clinical studies to treat rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
and type I. diabetes. Current therapeutic research areas in the treatment for DM include: long-term physical exercise, hot tube therapy (HTT), and alfalfa-derived HSP70 (aHSP70).
Hsp90 inhibitors are another possible treatment for autoimmunity, because hsp90 is necessary for proper folding of many pro-inflammatory proteins (components of PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
and 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.
Classification
The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33
Hsp33 protein is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localized protein with highly reactive cysteines that respond ...
, 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 bel ...
, HSP70
The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an import ...
/HSP110, HSP90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
, HSP100, and the small heat-shock proteins (sHSP
The heat shock protein Hsp20 family, also known as small heat shock proteins (sHSPs), is a family of heat shock proteins.
Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of protei ...
s). 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-chaperone
Co-chaperones are proteins that assist chaperones in protein folding and other functions. Co-chaperones are the non-client binding molecules that assist in protein folding mediated by Hsp70 and Hsp90. They are particularly essential in stimulation ...
s, and heat shock proteins not listed. In addition, many of these proteins may have multiple splice variants (Hsp90α and Hsp90β, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70).
See also
* Cellular stress response Cellular stress response is the wide range of molecular changes that cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stress responses can also be caused b ...
* Chaperone
* Chaperonin
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 bel ...
* Co-chaperone
Co-chaperones are proteins that assist chaperones in protein folding and other functions. Co-chaperones are the non-client binding molecules that assist in protein folding mediated by Hsp70 and Hsp90. They are particularly essential in stimulation ...
* FourU thermometer
__NOTOC__
FourU thermometers are a class of non-coding RNA thermometers found in ''Salmonella''. They are named 'FourU' due to the four highly conserved uridine nucleotides found directly opposite the Shine-Dalgarno sequence on hairpin II (''pict ...
* Hsp90 cis-regulatory element
The Hsp90 cis regulatory element is an RNA element (RNA thermometer) found in the 5' UTR of the ''Drosophila'' hsp90 mRNA. It is required for increased translation
Translation is the communication of the meaning of a source-language t ...
* ROSE element
* HSF1
Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the ''HSF1'' gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regul ...
References
External links
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{{DEFAULTSORT:Heat Shock Protein