In response to many stresses, including heat, oxidizing conditions, and exposure to toxic compounds, all cells produce a common set heat shock proteins (Hsps). Experiments in E. coli, yeast, fruit flies and mice have shown that increased expression of these proteins can protect the organism against stress-induced damage. The classic phenomenon of acquired thermotolerance led to the identification of the major classes of heat shock proteins in E. coli. Cells given a non-lethal preshock at 42 oC subsequently survive an otherwise lethal exposure to 46 oC. The preshocked cells stopped synthesis of the normal spectrum of proteins and began to synthesize a few proteins at high level.
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A very similar response occurs in all organisms. Increased expression of Hsps is mediated at multiple levels, mRNA synthesis, mRNA stability, and translation efficiency. Elevated synthesis of Hsps persists only through the initial period of stress. Even if the organism continues to be exposed to high temperature after the initial shock, Hsp expression drops, and Hsp levels return to normal. The heat shock response is distinct from adaptive responses that an organism may undergo when its environment changes gradually.
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Most, but not all, heat shock proteins are molecular chaperones. Molecular chaperones bind and stabilize proteins at intermediate stages of folding, assembly, translocation across membranes and degradation. Heat shock proteins have been classified by molecular weight, for example, Hsp70 for the 70 kDa heat shock protein.
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Hsp functions are required at normal temperatures, but the level of expression is reduced, and the identity of the Hsp may be different. In E. coli, Hsp70 is expressed at much reduced level in unstressed conditions, but it plays an important role in export of proteins to the periplasm and in protein degradation.
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Hsp70 cohort: Hsp40 Function, etc: ATPase; stabilizes proteins prior to complete folding, transport across membranes and proteolysis; found associated with misfolded and unassembled proteins, e.g., mutant p53 in cytosol or immunoglobulin heavy chains in ER of cells that don't make light chains; homologs in mitochondria and chloroplasts
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Heat Shock Proteins and Disease
Despite the obvious importance of stress responses, only recently has scrutiny focused on the role of heat shock proteins in the control of disease pathology and in the survival and virulence of pathogens. Knowlege about Hsp functions in bacteria is much further advanced than in eukaryotes, but already some hints of Hsp involvement in mammalian diseases have emerged. Here is a list of phenomena.
- Viral infection induces Hsp expression. Bacterial viruses use Hsps to facilitate takover of the cellular DNA replication machinery, and they employ Hsps for assembly of virus particles. In eukaryotes, heat shock proteins associate with key viral products, such as simian virus 40 (SV40) T-antigen, that control cell cycle progression and cause tissue transformation (cancer).
- Oxidative stress induces Hsp expression. Immune cells release nitric oxide and superoxide in the attack on invading cells. Host cells express Hsps to protect against oxidative damage. Unfortunately, the pathogens also mount a protective response with massive overproduction of Hsps.
- Hsp70 conveys peptide antigens for presentation to the immune system. Similar to its role in delivery of newly-synthesized proteins to the mitochondrion and ER, Hsp70 delivers peptides to the endoplasmic reticulum and proteins to the lysosome. Peptides generated by the proteasome in the cytoplasm are transported through the ER membrane via TAP transporters, loaded into class I major histocompatibility (MHC) proteins, and presented to CD8 cytotoxic T-cells. Peptides generated by acid hydrolases in the lysosomes are loaded into class II MHC proteins and presented to CD4 helper T-cells.
- Hsps are immunodominant antigens. Since they are so abundantly expressed, Hsps swamp the immune system with epitopes. Despite that they are highly conserved proteins, sufficient sequence divergence allows the mammalian immune system to avoid tolerance of Hsps. In some cases, anti-Hsp responses are protective. In other cases, anti-Hsp responses are thought to initiate or propagate autoimmune disease by cross-reacting with self Hsps. In still other cases, a response against self Hsp (Hsp60) paradoxically suppresses autoimmune disease symptoms!
- Emotional as well as mechanical stresses induce Hsp expression. When rats are physically restrained, their vascular endothelial cells express elevated levels of Hsp70. The response has been linked to an abrupt increase in blood pressure. [wj- it seems a jump in logic to say the rise in bp is necessarily from emotional stress rather than also from effort of struggling, for example, which would also increase bp... on the other hand this could possibly provide cellular support for the idea of various forms of stress leading to a common endpoint, which I have always felt was lacking and not explained by the cortisol theory]
- Elevated Hsp70 expression protects against cardiac failure. Hearts of transgenic mice that express elevated Hsp70 sustain less damage as a result of an experimental ischemic event.
- Hsp100 is necessary for propagation of prions in yeast. Aggregates of the Sup35 protein propagate themselves in a reaction that depends on yeast Hsp100. Although mammalian prions are composed of an unrelated protein, experiments with transgenic mice suggest that the species barrier is at least partly imposed by interactions between the prion proteins and a host factor that could be a molecular chaperone.
- Neurons are acutely sensitive to stress, possibly because they exhibit little or no stress response. In contrast, glia and other non-neuronal cells exhibit a robust stress response. Some evidence indicates that a specific mechanism transports Hsps from support cells to neurons during stress.
