It is demonstrated experimentally that addition of proteins that are themselves resistant to denaturation by heat or ethanol can nonspecifically stabilize other proteins that are ordinarily highly susceptible to inactivation. It is proposed that the diffusion-limited rate with which unfolded protein molecules encounter each other and become irreversibly crosslinked is reduced in the presence ofsubstantial concentrations ofan unreactive globular protein. We suggest that one of the functions of heat shock proteins, which are synthesized in large amounts after exposure of cells to increased temperature and other forms of stress, may be to stabilize other proteins kinetically in a similarly nonspecific fashion.When exposed to sufficiently high temperatures, cells die (as measured by reproductive assay) at a rate which, after an initial lag period, may be described by a first-order decay law. Although the cause of cell death is not definitely known, various pieces of indirect evidence suggest that the irreversible loss of vital protein structure and associated function is a major factor (1, 2). When cells are pretreated by exposure to increased but nonlethal temperatures or by brief exposure to lethal temperatures followed by a period ofrecovery, the treated cells exhibit a dramatically enhanced rate of survival upon subsequent exposure to lethal temperatures. This phenomenon is referred to as "acquired thermotolerance" (3).The mechanism by which cells acquire increased tolerance to thermal stress is unknown, but attention recently has focused on the possible role of heat shock proteins (hsp), a small number ('16) of specific proteins that are transcriptionally induced and synthesized in great quantity after exposure to elevated temperature ("heat shock") (4-6). The synthesis of hsp has been studied extensively as a model of gene regulation, particularly in Drosophila (6) but also in various organisms throughout the phylogenetic tree (4,(7)(8)(9)(10)(11)(12). Recently it has been shown that the time scale for the appearance and disappearance of hsp parallels the expression ofacquired thermotolerance in various cell types (11-13) and that thermotolerance is not acquired after heat shock if synthesis of hsp is inhibited (8,12,14).The synthesis of hsp is also induced by noxious stimuli other than heat shock, including arsenite (6, 14), oxygen deprivation (4, 6), and ethanol (14). It has been demonstrated that preliminary exposure to ethanol results in subsequently acquired resistance not only to ethanol but also to thermal stress (15). Moreover, thermal pretreatment appears to result in increased tolerance to ethanol (16). These findings suggest that hsp may play a role in a generalized cellular adaptation to stress.hsp are quite widespread within the cell. Low molecular weight hsp bind predominantly to nuclear chromatin; higher molecular weight hsp are found predominantly in the cytoplasm (4,7,(17)(18)(19)(20)(21)(22). No enzymatic activity of hsp has yet been identified (6, 7).Here we propose that hsp can con...