Regulation of Superoxide by BAP31 through Its Effect on p22^phox and Keap1/Nrf2/HO‐1 Signaling Pathway in Microglia

Abstract

Reactive oxygen species (ROS) production by activation of microglia is considered to be a major cause of neuronal dysfunction, which can lead to damage and death through direct oxidative damage to neuronal macromolecules or derangement of neuronal redox signaling circuits. BAP31, an integral ER membrane protein, has been defined as a regulatory molecule in the CNS. Our latest studies have found that BAP31 deficiency leads to activation of microglia. In this study, we discovered that BAP31 deficiency upregulated LPS-induced superoxide anion production in BV2 cells and mice by upregulating the expression level of p22phox and by inhibiting the activation of Nrf2-HO-1 signaling. Knockdown of p22phox/keap1 or use of an NADPH oxidase inhibitor (apocynin) reversed the production of superoxide anion and inflammatory cytokines, which then reduced neuronal damage and death in vitro and in vivo. These results suggest that BAP31 deficiency contributes to microglia-related superoxide anion production and neuroinflammation through p22phox and keap1. Furthermore, the excess superoxide anion cooperated with inflammatory cytokines to induce the damage and death of neurons. Thus, we determined that BAP31 is an important regulator in superoxide anion production and neuroinflammation, and the downstream regulators or agonists of BAP31 could therefore be considered as potential therapeutic targets in microglial-related superoxide anion production and neuroinflammation.

HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer

“…Increased lipid peroxidation and enhanced ROS are characteristics of ferroptosis, making it different from other forms of cell death such as apoptosis, necrosis, and autophagy [ 26 ]. It has been reported that BAP31 – an integral ER membrane protein – is involved in ROS production through p22 phox and Keap1/Nrf2/HO-1 signaling pathway in microglia [ 27 ]. However, whether BAP31 plays a role in ferroptosis remains uncertain.…”