Heat shock proteins (HSP) are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress.[1] 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).[2] 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.[3] The small 8-kilodalton protein ubiquitin, which marks proteins for degradation, also has features of a heat shock protein.[4]
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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, Ritossa reported that heat and the metabolic uncoupler dinitrophenol induced a characteristic pattern of puffing in the chromosomes of Drosophila.[5][6] This discovery eventually led to the identification of the heat-shock proteins (HSP) or stress proteins whose expression these puffs represented. Increased synthesis of selected proteins in Drosophila cells following stresses such as heat shock was first reported in 1974.[7]
Beginning in the mid-1980s, 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. Therefore, the study of stress proteins has undergone explosive growth.
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.[8]
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 do not fold and cannot insert correctly into the outer membrane. They accumulate in the periplasmic space. These OMP's are detected by DegS, an inner membrane protease, that passes the signal through the membrane to the sigmaE transcription factor.[9] 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.[10]
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.[11][12]
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.[13]
Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation.[14]
A downstream 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.[15] 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.[16]
Hsp27 is a major phosphoprotein during muscle contraction. Hsp27 functions in smooth muscle migration and appears to serve an integral role.[17]
Extracellular and membrane bound heat-shock proteins, especially Hsp70 are involved in binding antigens and presenting them to the immune system.[18]
Heat Shock Factor 1 (HSF1) is a transcription factor that is involved in the upregulation of Hsp70 protein expression.[19] 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.[20]
Given their role in antigen presentation,[18] HSPs are useful as immunologic adjuvants in boosting the response to a vaccine.[21] Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system.[22] Therefore HSPs may be useful for increasing the effectiveness of cancer vaccines.[18][23]
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.[24] The potent Hsp90 inhibitor 17-AAG is currently in clinical trials for the treatment of several types of cancer.[25]
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.[26]
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).[7]
| Approximate molecular weight
(kDa) |
Prokaryotic proteins | Eukaryotic proteins | Function |
|---|---|---|---|
| 10 kDa | GroES | Hsp10 | |
| 20-30 kDa | GrpE | The HspB group of Hsp. Eleven members in mammals including Hsp27, HSPB6 or HspB1 [27] | |
| 40 kDa | DnaJ | Hsp40 | Co-factor of Hsp70 |
| 60 kDa | GroEL, 60kDa antigen | Hsp60 | Involved in protein folding after its post-translational import to the mitochondrion/chloroplast |
| 70 kDa | DnaK | 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. |
| 90 kDa | HtpG, C62.5 | The HspC group of Hsp including Hsp90, Grp94 | Maintenance of steroid receptors and transcription factors |
| 100 kDa | ClpB, ClpA, ClpX | Hsp104, Hsp110 | 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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