Ménage à Trois in stress: DAMPs, redox and autophagy

Cells have evolved rather sophisticated mechanisms to deal with stress positively and efficiently. Accumulation of reactive oxygen species (ROS), release of damage-associated molecular pattern molecule (DAMPs), and autophagy induction, are three inter-related processes occurring during most if not all cellular adaptations to stress. They influence each other reciprocally, initiating individual pathways, mediating and/or inducing effector mechanisms and modifying cellular function. High-mobility group box 1 (HMGB1), is a prototypic DAMP molecule, with various roles depending on its compartmental localization (nuclear, cytosolic, extracellular), well-defined but rather promiscuous binding partners, and the redox status within or without the cell. Typically, HMGB1 serves as a redox sensor, where redox modification also defines its translocation, release and activity, illustrative of the coordinate and multiply determined paths involved in the response to cell stress. Since DAMPs, redox and autophagy are essential and multifaceted in their roles in host defense, inflammation, and homeostasis, understanding how they interact and coordinate various signaling pathways to adjust to the stressful environment is important in the development of various potential therapeutic strategies, including application to patients with cancer.