Some of the most challenging stress conditions that organisms encounter during their lifetime involve the transient accumulation of reactive oxygen and chlorine species. Extremely reactive to amino acid side chains, these oxidants cause widespread protein unfolding and aggregation. It is therefore not surprising that cells draw on a variety of different strategies to counteract the damage and maintain a healthy proteome. Orchestrated largely by direct changes in the thiol oxidation status of key proteins, the response strategies involve all layers of protein protection. Reprogramming of basic biological functions helps decrease nascent protein synthesis and restore redox homeostasis. Mobilization of oxidative stress-activated chaperones and production of stress-resistant non-proteinaceous chaperones prevent irreversible protein aggregation. Finally, redox-controlled increase in proteasome activity removes any irreversibly damaged proteins. Together, these systems pave the way to restore protein homeostasis and enable organisms to survive stress conditions that are inevitable when living an aerobic lifestyle.

Summary Exposure of cells to reactive oxygen species (ROS) causes a rapid and significant drop in intracellular ATP-levels. This energy depletion negatively affects ATP-dependent chaperone systems, making ROS-mediated protein unfolding and aggregation a potentially very challenging problem. Here we show that Get3, a protein involved in ATP-dependent targeting of tail-anchored (TA) proteins under non-stress conditions, turns into an effective ATP-in dependent chaperone when oxidized. Activation of Get3’s chaperone function, which is a fully reversible process, involves disulfide bond formation, metal release and its conversion into distinct, higher oligomeric structures. Mutational studies demonstrate that the chaperone activity of Get3 is functionally distinct from and likely mutually exclusive with its targeting function, and responsible for the oxidative stress sensitive phenotype that has long been noted for yeast cells lacking functional Get3. These results provide convincing evidence that Get3 functions as a redox regulated chaperone, effectively protecting eukaryotic cells against oxidative protein damage.

Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, or severe heat stress, which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. Here, we review recent advances in identifying and characterizing stress-activated chaperones, which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the posttranslational mechanisms by which these chaperones sense stress and consider the role intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets.