Cellular redox homeostasis is precisely balanced by generation and elimination of reactive oxygen species (ROS). ROS are not only capable of causing oxidation of proteins, lipids and DNA to damage cells but can also act as signaling molecules to modulate transcription factors and epigenetic pathways that determine cell survival and death. Hsp70 proteins are central hubs for proteostasis and are important factors to ameliorate damage from different kinds of stress including oxidative stress. Hsp70 members often participate in different cellular signaling pathways via their clients and cochaperones. ROS can directly cause oxidative cysteine modifications of Hsp70 members to alter their structure and chaperone activity, resulting in changes in the interactions between Hsp70 and their clients or cochaperones, which can then transfer redox signals to Hsp70-related signaling pathways. On the other hand, ROS also activate some redox-related signaling pathways to indirectly modulate Hsp70 activity and expression. Post-translational modifications including phosphorylation together with elevated Hsp70 expression can expand the capacity of Hsp70 to deal with ROS-damaged proteins and support antioxidant enzymes. Knowledge about the response and role of Hsp70 in redox homeostasis will facilitate our understanding of the cellular knock-on effects of inhibitors targeting Hsp70 and the mechanisms of redox-related diseases and aging.

Hsp70 can buffer different kinds of stress including oxidative stress to contribute to redox homeostasis. Hsp70 members are important antioxidative components in eliminating damaged oxidized proteins and support antioxidative enzymes. Under oxidative stress, Hsp70 members will inevitably undergo oxidization, resulting in changes in their structure and chaperone activity. However, cysteine modifications often downregulate the chaperone activity of Hsp70, which is disadvantageous for dealing with protein damage due to oxidation. From this point of view, cysteine residues in Hsp70 are not conducive towards Hsp70 exerting its antioxidative functions. At the same time, only very few Hsp70 members do not contain any cysteine residues, and the number of cysteine residues in Hsp70 increases with evolution, suggesting important roles of cysteine residues in Hsp70. Hsp70 members can sense redox by cysteine modifications, then transfer redox signals by modulating the interaction between Hsp70 members and their clients. Hsp70 members are involved in cellular signaling due to the fact that their clients include key molecules in signaling pathways, including Hsf1 and Akt1. Cochaperones also guide Hsp70 members within different cellular processes, such as CHIP, acting as a link between Hsp70 and the ubiquitin–proteasome system (UPS) for degradation of Hsp70 clients. Thus, cysteine modifications of Hsp70 also change the fate of the clients by modifying the cooperation between Hsp70 and cochaperones. Therefore, cysteine modifications of Hsp70 may act to amplify the transfer of redox signaling to a broader range of proteins, achieving greater antioxidative potential in a shorter time and restoring the cellular environment by multiple pathways. As a consequence, Hsp70 proteins are expressed much more rapidly through different signaling pathways, and the newly synthesized Hsp70 proteins are not oxidized and have normal chaperone activity to deal with the damaged proteins that have accumulated during oxidative stress. Thus, combining an in-depth understanding of the basic principles of Hsp70 systems (including the relationship between the structure and function of Hsp70, the interaction between Hsp70 and its cochaperones, and the interaction between Hsp70 and its clients) and the extensive exploration of redox-related signaling pathways involving Hsp70 will lead to a fuller understanding of Hsp70 function in redox homeostasis.