Heat-shock proteins and molecular chaperones: implications for pathogenesis, diagnostics, and therapeutics.

Cells react to physical (e.g., heat) or chemical (e.g., anoxia, low pH) stressors, mounting a stress (heat-shock) response. Most genes are turned down or off, while a few are activated. The latter encode the stress or heat-shock proteins (Hsps), whose levels increase in stressed cells. Various Hsps are molecular chaperones. These, and other molecular chaperones that are not Hsps, help the other cellular proteins to achieve their native state (correct folding or functional conformation), reach their final destination (e.g., the endoplasmic reticulum or the mitochondria), resist denaturing by stressors, and regain the native state after partial denaturation. Thus the Hsps and molecular chaperones occupy the stage's center whenever and wherever there is cellular and tissue injury caused by local or systemic stressors via protein damage. This feature, their participation in protein folding and transport, and their evolutionary conservation within the three phylogenetic domains, strongly suggest a vital role for Hsps and molecular chaperones. Their importance in pathogenesis, and as diagnostic markers and prognostic indicators, is beginning to be appreciated. The role of Hsps and molecular chaperones in cell recovery from injury by a variety of noxae of clinical and surgical relevance is also being assessed. Consequently, the potential of these molecules (and corresponding genes) as targets for treatment or as therapeutic tools is emerging and is being explored. Stroke, myocardial infarction, inflammatory syndromes, infectious and parasitic diseases, autoimmune disorders, cancer, and aging are but some examples of conditions in which Hsps and molecular chaperones are being scrutinized. The era of Hsp and molecular chaperone pathology has dawned. It is likely that genetic and acquired defects of Hsp and molecular chaperone structure and function will be identified, and will play a primary, or auxiliary but determinant, role in disease.