Heat shock protein
Heat shock proteins (HSPs) are a family of
Heat shock proteins are named according to their molecular weight. For example,
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
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
Upregulation in stress
Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental
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
Some bacterial heat shock proteins are upregulated via a mechanism involving
Petersen and Mitchell[17] 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.[18] A mild heat shock pretreatment of the same kind that protects against death from subsequent heat shock also prevents death from exposure to cold.[18]
Role as chaperone
Several heat shock proteins function as intra-cellular
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.[21]
Cardiovascular
Heat shock proteins appear to serve a significant cardiovascular role. Hsp90,
Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation.[23]
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.[24]
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.[25]
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.
Hsp27 is a major phosphoprotein during women's contractions. Hsp27 functions in small muscle migrations and appears to serve an integral role.[28]
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.[29]
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.[29] In the case of gp96 it is not clear whether it can bind peptides in vivo, although its peptide-binding site has been found.[30] But gp96 immune function could be peptide-independent, because it is involved in proper folding of many immune receptors, like TLR or integrins.[29]
Apart from that, HSPs can stimulate immune receptors and are important in proper folding of proteins involved in pro-inflammatory signaling pathways.[30][31]
Antigen presentation
HSPs are indispensable components of antigen presentation pathways - the classical ones[29][32][33] and also cross-presentation[30] and autophagy.[33]
MHCI presentation
In the simplified view of this pathway HSPs are usually not mentioned: antigenic peptides are generated in
But HSPs play an important part in transfer of unfolded proteins to proteasome and generated peptides to MHCI.[29] 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, 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.[29]
MHCII presentation
In MHCII presentation, HSPs are involved in clathrin-dependent endocytosis.[33] 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).[30]
Autophagy
HSPs are involved in classical macroautophagy, when protein aggregates are enclosed by double membrane and degraded afterwards.[33] They are also involved in a special type of autophagy called chaperone-mediated autophagy, when they enable cytosolic proteins to get into lysosomes.[33]
Cross-presentation
When HSPs are extracellular, they can bind to specific receptors on
LOX-1 and SRECI when stimulated guide HSPs with their associated peptides into cross-presentation. LOX-1 binds mainly
The relevance for this type of cross-presentation is high especially in tumour-immunosurveillance.[30][29] 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.[29]
Damage-associated molecular patterns
Extracellular heat-shock proteins can be sensed by the immunity as damage-associated molecular patterns (DAMPs).[30] 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.[29][32] 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.[34]
Heat-shock proteins can signal also through
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.[30]
Another possibility is release of HSPs during cell necrosis, or secretion of HSPs in exosomes.[30] During special types of apoptotic cell death (for example induced by some chemotherapeutics), HSPs can also appear on the extracellular side of plasma membrane.[32]
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.[30]
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
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).[35][29]
Lens
Alpha
Clinical significance
HSF 1
Diabetes mellitus
Diabetes mellitus (DM) is a immune-disease characterized by the presence of hyperglycemia. Typically these symptoms are brought about by insulin deficiency.[40] However, there have been many recent articles alluding to a correlation between hsp70, in some cases hsp60, and DM.[41][42] Another recent article discovered the ratio of ehsp70 and ihsp70 could have an effect on DM, leading to a sufficient biomarker.[43] Serum levels of hsp70 have also been shown to increase over time in patients with diabetes.[44]
Cancer
HSP expression plays a pivotal role in cancer identification. Recent discoveries have shown that high concentrations of eHSP can indicate the presence of contentious tumors.[45] Additionally, HSPs have been shown to benefit oncologist in oral cancer diagnosis.[46] Using techniques such as dot immunoassay and ELISA test researchers have been able to determine that HSP-specific phage antibodies could be beneficial in-vitro cancer diagnosis markers.[47] 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.[48]
Applications
Cancer vaccines
Given their role in presentation,[49] HSPs are useful as immunologic adjuvants (DAMPS) in boosting the response to a vaccine.[50] Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system.[51] In a recent study published by Sedlacek et al., HSP was shown to effect different signaling pathways involved in carcinogenesis responses such as STAT1 activation, gp96-activated macrophages, and activation of NK cells.[52] Therefore, HSPs may be useful for increasing the effectiveness of cancer vaccines.[49][53]
Also isolated HSPs from tumor cells are able to act as a specific anti-tumor vaccine by themselves.
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.
Autoimmunity treatment
Acting as
Hsp90 inhibitors are another possible treatment for autoimmunity, because hsp90 is necessary for proper folding of many pro-inflammatory proteins (components of PI3K, MAPK and NF-kB cascades).[31]
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.[60]
Classification
The principal heat-shock proteins that have chaperone activity belong to five conserved classes:
Approximate molecular weight
( kDa )
|
Prokaryotic proteins | Eukaryotic proteins | Function |
---|---|---|---|
10 kDa | GroES | Hsp10 (HSPD) | Co-factor of Hsp60 |
20–30 kDa | GrpE | In humans: GRPE1, GRPE2 | Co-factor of DnaK/Hsp70, only for bacterial or mitochondrial/chloroplastic forms |
20-30 kDa | Hsp20 | Human HSPB genes. Eleven members in mammals including Hsp27, HSPB6 or HspB1[61] | Chaperones |
40 kDa
|
DnaJ | Hsp40 (DNAJ*; three subfamilies in humans) | Co-factor of Hsp70 |
60 kDa | GroEL, 60kDa antigen | Hsp60 (HSPE) | Involved in protein folding after its post-translational import to the mitochondrion/chloroplast; a chaperonin |
70 kDa | DnaK | Human HSPA genes. Includes Hsp71 (HSPA8), Hsp72 (HSPA1A), Grp78 (BiP, HSPA5); Hsx70 (HSPA1B) found only in primates. Hsp110 genes are derived from this superfamily and are coded HSPH1 through 4.[61] |
Protein folding and unfolding. Provides thermotolerance to cell on exposure to heat stress and protects against H2O2.[62] Also prevents protein folding during post-translational import into the mitochondria/chloroplast. Hsp110 provides tolerance of extreme temperature. |
90 kDa | HtpG, C62.5 | Human HSPC genes. Includes Hsp90, Grp94 (HSPC4) | Maintenance of steroid receptors and transcription factors |
100 kDa | ClpB, ClpA, ClpX | Hsp104 (CLPB) | Unfolding of insoluble protein aggregates; co-factor of DnaK/Hsp70 |
Although the most important members of each family are tabulated here, some species may express additional chaperones,
See also
- Cellular stress response
- Chaperone
- Chaperonin
- Co-chaperone
- Cold-shock domain
- FourU thermometer
- Hsp90 cis-regulatory element
- ROSE element
- HSF1
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External links
- Heat-Shock+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)