HOW THE CELL COPES WITH STRESS AND THE FUNCTION OF HEAT-SHOCK PROTEINS

Virtually all cells, including the prokaryotic microorganisms and the highly differentiated eukaryotic cells in human tissues, contain a sma ll set of normally silent genes that are rapidly activated by a heat s hock that raises the temperature only 5 to 10% above that of the norma l physiologic range for that organism. Concomitantly, many active gene s are turned off. Other kinds of stress, such as exposure to alcohol o r other organic agents, heavy metals, oxidants, and agents capable of perturbing protein structure, produce a similar response, and many of these activate the same set of genes. The proteins encoded by these st ress-activated genes are called heat shock proteins (hsp). They are st rongly conserved in structure among widely divergent biologic species, and many function as ''molecular chaperones'' by forming transient co mplexes with partially folded or misfolded polypeptides so as to preve nt their irreversible denaturation. Most hsp are members of gene/prote in families, and isoforms are frequently found under normal physiologi c conditions in many compartments of the cell where they act also as c haperones, binding to a variety of polypeptides to facilitate folding, oligomerization, transport, metabolic activity, and degradation. Few of the polypeptide ''targets'' that complex with stress-induced forms of hsp have been identified, but a number of cellular components have been shown to be particularly stress sensitive. They include macromole cular complexes involved in the maintenance of chromosome replication and transcription, mRNA splicing, and ribosome assembly. Mitochondria and the intermediate filament network are also highly sensitive, where as the protein synthetic machinery and vesicles of the secretory pathw ay are relative stable to physiologic stress. The factors regulating h eat shock genes in the eukaryote are highly conserved among widely div ergent species and include promoters consisting of arrays of Short, in verted sequences in the DNA, caned the heat shock element, and heat sh ock factors, which are large polypeptides that occupy these promoters soon after the cell senses the temperature shift. The sensor(s) that s ignal the cell to initiate binding of heat shock factors to the heat s hock element, thereby activating gene transcription, have not been ide ntified, but misfolded proteins are postulated to play a key role in t his event. The response is also transient, and other factors down-regu late the system. Cells that have been mildly prestressed so that they contain significant levels of the hsp become tolerant to stress condit ions that would normally kill the cell. In this way, organisms survive environmental conditions that might otherwise prove fatal.