How the cell copes with stress and the function of heat shock proteins

Abstract

Virtually all cells, including the prokaryotic microorganisms and the highly differentiated eukaryotic cells in human tissues, contain a small set of normally silent genes that are rapidly activated by a heat shock that raises the temperature only 5 to 10% above that of the normal physiologic range for that organism. Concomitantly, many active genes are turned off. Other kinds of stress, such as exposure to alcohol or 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 stress-activated genes are called heat shock proteins (hsp). They are strongly conserved in structure among widely divergent biologic species, and many function as 'molecular chaperones' by forming transient complexes with partially folded or misfolded polypeptides so as to prevent their irreversible denaturation. Most hsp are members of gene/protein families, and isoforms are frequently found under normal physiologic conditions in many compartments of the cell where they act also as chaperones, 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 macromolecular 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, whereas the protein synthetic machinery and vesicles of the secretory pathway are relative stable to physiologic stress. The factors regulating heat shock genes in the eukaryote are highly conserved among widely divergent species and include promoters consisting of arrays of short, inverted sequences in the DNA, called the heat shock element, and heat shock factors, which are large polypeptides that occupy these promoters soon after the cell senses the temperature shift. The sensor(s) that signal the cell to initiate binding of heat shock factors to the heat shock element, thereby activating gene transcription, have not been identified, but misfolded proteins are postulated to play a key role in this event. The response is also transient, and other factors down-regulate the system. Cells that have been mildly prestressed so that they contain significant levels of the hsp become tolerant to stress conditions that would normally kill the cell. In this way, organisms survive environmental conditions that might otherwise prove fatal.