They were first described in relation to heat shock,[1] but are now known to also be expressed during other stresses including exposure to cold,[2] UV light[3] and during wound healing or tissue remodeling.
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.
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 initial biochemical finding gave rise to a large number of studies on the induction of heat shock and its biological role.
Heat shock proteins have been found in all species examined, from bacteria to humans, suggesting that they evolved very early and have an important 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.
Expression of the hspb4 gene, which codes for alpha crystallin, increases considerably in the lens in response to heat shock.
[13] 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 harmful materials (ethanol, arsenic, and trace metals, among many others), ultraviolet light, starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants) or water deprivation.
[19][20] Some members of the HSP family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance.
Recently, there are several studies that suggest a correlation between HSPs and dual frequency ultrasound as demonstrated by the use of LDM-MED machine.
[22] 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.
[29] Apart from that, HSPs can stimulate immune receptors and are important in proper folding of proteins involved in pro-inflammatory signaling pathways.
But HSPs play an important part in transfer of unfolded proteins to proteasome and generated peptides to MHCI.
[33] When HSPs are extracellular, they can bind to specific receptors on dendritic cells (DC) and promote cross-presentation of their carried peptides.
[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 scavenger receptors, which can either associate with TLRs, or activate pro-inflammatory intracellular pathways like MAPK or NF-kB.
[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.
HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of DMBA (7,12-dimethylbenzanthracene), a mutagen.
[38] Moreover, HSF1 inhibition by a potent RNA aptamer attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.
[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.
[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.
[55] 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.
[58] Acting as DAMPs, HSPs can extracellularly promote autoimmune reactions leading to diseases as rheumatoid arthritis or systemic lupus erythematosus.
[35] Current therapeutic research areas in the treatment for DM include: long-term physical exercise, hot tub therapy (HTT), and alfalfa-derived HSP70 (aHSP70).
[59] 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] 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.
[61] 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.