Structure and functions of cellular redox sensor HSCARG/NMRAL1, a linkage among redox status, innate immunity, DNA damage response, and cancer

Abstract

NmrA-like proteins are NAD(P) (H) interacting molecules whose structures are similar to that of short-chain dehydrogenases. In this review, we focus on an NADP(H) sensor, HSCARG (also named NMRAL1), which is a NmrA-like protein that is widely present in mammals, and provide a comprehensive overview of the current knowledge of its structure and physiological functions. HSCARG selectively binds to the reduced form of type II coenzyme NADPH via its Rossmann fold domain. In response to reduction of intracellular NADPH concentration, HSCARG transforms from homodimer to monomer and exhibits enhanced interactions with its binding partners. In the cytoplasm, HSCARG negatively regulates innate immunity through impairing the activities of NF-κB and RLR pathways. Besides, HSCARG regulates redox homeostasis via suppression of ROS and NO generation. Intensive and persistent oxidative stress leads to translocation of HSCARG from the cytoplasm to the nucleus, where it regulates the DNA damage response. Taken together, HSCARG functions as a linkage between cellular redox status and other signaling pathways and fine-tunes cellular response to redox changes.

Direct 3D Sampling of the Embryonic Mouse Head: Layer-wise Nanosecond Infrared Laser (NIRL) Ablation from Scalp to Cortex for Spatially Resolved Proteomics

“…50−52 Additionally, NMRAL1 (NmrA-like family domain-containing protein 1) is a largely unknown protein, and only a NADPH-binding function is assumed. 53 The results of our study confirm the potential to spatially resolve the proteomic signatures of embryonic mouse head structures and forebrain regions using NIRL-based 3D sampling and subsequent bottom-up proteomics. Direct ablation from a 3-dimensional tissue sample like the mouse head with an axial resolution of about 40 μm paves the way for numerous research questions focusing on spatial resolution in proteomics with the additional possibility to achieve even higher resolution.…”

“…Deficiency of this protein was shown to be related to psychiatric disorders. , APOE (Apolipoprotein E) is a protein expressed in the brain and is associated with astrocytic cells, which are in close proximity to the pial surface. − NMRAL1 and MTA1 were shown to be more abundant in layers 5–9 (Figure d). Whereas these proteins have not been reported in the context of cortical development yet, MTA1 (Metastasis-associated protein) is known to be expressed in different cancer types and to regulate the stability of the oncosuppressor p53. − Additionally, NMRAL1 (NmrA-like family domain-containing protein 1) is a largely unknown protein, and only a NADPH-binding function is assumed …”

Fungal P450 Deconstructs the 2,5-Diazabicyclo[2.2.2]octane Ring En Route to the Complete Biosynthesis of 21R-Citrinadin A

“…Having elucidated the key enzyme for breaking the bridged bicyclic system, we then focused on the remaining essential enzymes for post-modification of 10 . NmrA-like proteins were previously regarded as the transcriptional nitrogen metabolism repressor or redox-sensing regulators and usually show no catalytic function. − However, CtdP belonging to this family has been reported to participate in the DA reaction and reduce the iminium in a redox cycle with NADP + . Considering the high sequence identity (42.5%) between CtdR and CtdP and the accumulation of the iminium-containing compound 19 in Δ ctdR mutant, CtdR was proposed as the key enzyme catalyzing iminium reduction.…”

Mitonuclear mismatch alters nuclear gene expression in naturally introgressed Rhinolophus bats

“…One upregulated gene in the cochlea of the mismatched group, SLC40A1 , encodes an iron transporter and can regulate cell oxidative stresses [ 79 ]. Among two genes ( CA3 and NMRAL1 ) showing upregulation in the small intestine of the mismatched group, CA3 encodes carbonic anhydrase 3, which functions as an antioxidant and has been proposed to have protective roles against oxidative damage [ 80 ], while NMRAL1 (also called HSCARG) acts as a cellular redox sensor and can regulate DNA damage response caused by severe oxidative stress [ 81 ]. Finally, in contrast to other tissues, almost all DEGs identified in the liver are downregulated in the mismatched group, although it is unclear whether these genes function in oxidative stress.…”