Reactive Oxygen Species (ROS) Signaling: Regulatory Mechanisms and Pathophysiological Roles

Reactive oxygen species (ROS) are highly reactive molecules generated during mitochondrial respiration and under various environmental stresses, and cause damage to DNA, proteins, and lipids, which is linked to a wide variety of pathologies. However, recent studies have revealed the physiological importance of ROS as signaling molecules, which play crucial roles in the maintenance of cellular functions and homeostasis. According to the extent and duration of ROS generation, ROS-mediated oxidation-reduction (redox) signaling (ROS signaling) is tightly regulated by various molecules and post-translational modifications (PTMs), for inducing appropriate cellular responses. Dysregulation of ROS signaling causes cellular malfunctions, which are also linked to various diseases, such as cancer, neurodegeneration and inflammatory diseases. In this review, we focus on a ROS-responsive protein kinase apoptosis signal-regulating kinase 1 (ASK1) that belongs to the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, and activates the c-jun N-terminal kinase (JNK) and p38 MAP kinase pathways, which consequently induces various cellular responses, including apoptosis and inflammation. Here, we introduce a novel regulatory mechanism and the pathophysiological significance of ASK1 activation. We found that an E3 ubiquitin ligase TRIM48 orchestrates fine-tuning of ROS-induced ASK1 activation mediated by multiple types of PTMs, including ubiquitination, methylation, and phosphorylation. We also found that trans-fatty acids (TFAs) enhance ROS-dependent ASK1 activation induced by extracellular ATP, a damage-associated molecular pattern (DAMP), and thereby promotes apoptosis, which possibly contributes to the pathogenesis of TFA-related diseases including atherosclerosis. Thus, this review provides recent advances in the study of ROS signaling, especially ROS-ASK1 signaling pathway.