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Proteins containing non‐native disulfide bonds generated by oxidative stress can act as signals for the induction of the heat shock response

While oxidative stress can induce a heat shock response, the primary signals that initiate activation have not been identified. To identify such signals, HepG2 and V 79 cells were exposed to menadione, a compound that redox‐cycles to generate superoxide. The oxidative stress generated by menadione resulted in oxidation of protein thiols in a dose‐dependent manner. This was followed by protein destabilization and denaturation, as determined by differential scanning calorimetry of whole cells. To directly evaluate the effect of non‐native disulfides on protein conformation, Ca2+‐ATPase, isolated from rabbit sarcoplasmic reticulum, was chemically modified to contain non‐native intermolecular or glutathione (GHS)‐mixed disulfides. Differential scanning calorimetry profiles and 1‐anilinonaphthalene‐8‐sulfonic acid fluorescence indicated that formation of non‐native disulfides produced protein destabilization, denaturation, and exposure of hydrophobic domains. Cellular proteins shown to contain oxidized thiols formed detergent‐insoluble aggregates. Cells treated with menadione exhibited activation of HSF‐1, accumulated Hsp 70 mRNA, and increased synthesis of Hsp 70. This work demonstrates that formation of physiologically relevant, non‐native intermolecular and GSH‐mixed disulfides causes proteins to destabilize, unfold such that hydrophobic domains are exposed, and initiate a signal for induction of the heat shock response. J. Cell. Physiol. 171:143–151, 1997. © 1997 Wiley‐Liss, Inc.