The structure and function of the cellular redox sensor HSCARG/NMRAL1: fifteen years of exploration from three-dimensional structure to biological function

<p indent="0mm">HSCARG (also known as NmrA-like family redox sensor 1, NMRAL1) belongs to the NmrA-like protein family. Through the determination of the three-dimensional crystal structure of HSCARG, we demonstrated for the first time that it is a NADP(H) sensor widely present in mammalian cells. Our research on its functions indicates that HSCARG plays a pivotal role in regulating cellular redox homeostasis, innate immunity, DNA damage repair (DDR), and tumor development. HSCARG selectively binds to the reduced form of type II coenzyme NADPH through its N-terminal Rossmann fold domain. When the intracellular concentration of NADPH decreases, HSCARG transitions from homodimer to monomer, enhancing its interactions with interacting proteins. In the cytoplasm, HSCARG negatively regulates innate immunity by inhibiting the activity of the NF-κB (nuclear factor-kappa B) and RLR (RIG-I-like receptor) signaling pathways. Furthermore, HSCARG regulates redox balance by suppressing the production of reactive oxygen species (ROS) and nitric oxide (NO). Persistent oxidative stress causes the cytoplasm-to-nucleus translocation of HSCARG, where it modulates the efficiency of DNA damage repair by affecting the ubiquitination of histone H2A and PCNA (proliferating cell nuclear antigen). In summary, HSCARG acts as a linkage between cellular redox status and other signaling pathways to finely tune the cellular response to redox changes. This review primarily summarizes our exploration and understanding of the structure and functions of the redox cellular sensor HSCARG over the past fifteen years.