Heat shock proteins (HSP) are a family of proteins that are 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 function 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).
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.
Beginning in the mid-1960s, investigators recognized that many HSPs function as molecular chaperones and thus play a critical role in protein folding, intracellular trafficking of proteins, and coping with proteins denatured by heat and other stresses. Since that time, the study of stress proteins has undergone explosive growth.
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 toxins (ethanol, arsenic, trace metals, and ultraviolet light, among many others), 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.
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.
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".
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.
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.
Extracellular and membrane bound heat-shock proteins, especially Hsp70 are involved in binding antigens and presenting them to the immune system.
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.
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 DMBA (7,12-dimethylbenzanthracene), a mutagen. Moreover, HSF1 inhibition by a potent RNA aptamer attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.
Cancer vaccine adjuvant
Given their role in antigen presentation, HSPs are useful as immunologic adjuvants 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.
Intracellular heat shock proteins are highly expressed in cancerous cells and are essential to the survival of these cell types. Hence small molecule inhibitors of HSPs, especially Hsp90 show promise as anticancer agents. The potent Hsp90 inhibitor 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.
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.
The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33, HSP60, HSP70, HSP90, HSP100, and the small heat-shock proteins (sHSPs).
|Approximate molecular weight
||The HspB group of Hsp. Eleven members in mammals including Hsp27, HSPB6 or HspB1
||Co-factor of Hsp70
||GroEL, 60kDa antigen
||Involved in protein folding after its post-translational import to the mitochondrion/chloroplast
||The HspA group of Hsp including Hsp71, Hsp70, Hsp72, Grp78 (BiP), Hsx70 found only in primates
||Protein folding and unfolding, provides thermotolerance to cell on exposure to heat stress. Also prevents protein folding during post-translational import into the mitochondria/chloroplast.
||The HspC group of Hsp including Hsp90, Grp94
||Maintenance of steroid receptors and transcription factors
||ClpB, ClpA, ClpX
||Tolerance of extreme temperature
Although the most important members of each family are tabulated here, it should be noted that some species may express additional chaperones, co-chaperones, 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).
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