Our immune system relies on specialized cells, such as neutrophils and macrophages, to detect and eliminate invading microbes. One of the most powerful weapons used by these cells is a multicomponent molecular machinery known as NADPH oxidase. Upon activation, this enzyme generates reactive oxygen species (ROS), highly reactive molecules that contribute to the destruction of bacteria and fungi engulfed by immune cells. A key component of this molecular machine is a glycosylated membrane heterodimer called flavocytochrome b558 composed of two subunits, NOX2 and p22phox. The synthesis and assembly of this complex within the cell is a complex process involving multiple distinct post-translational modifications, cofactors binding, heterodimerization of both proteins, maturation and its subsequent transport to the cellular membranes, where the enzyme becomes functionally active.
This review just published in Antioxidants focuses on the role of EROS (for Essential for Reactive Oxygen Species), a recently discovered protein which has emerged as an important helper—or molecular “chaperone”—in the synthesis and maturation process of the flavocytochrome b558. EROS seems to interact with NOX2 at an early stage of its synthesis and protects it from degradation. This allows NOX2 to mature correctly and eventually become part of the functional flavocytochrome b558 complex.
The authors bring together decades of research on flavocytochrome b558 biosynthesis with recent structural studies, including advances in cryo-electron microscopy. These studies provide a more detailed picture of how NOX2, p22phox and EROS interact and how the NADPH oxidase is assembled and activated. Ultimately, elucidating this molecular interplay may help clarify how specific genetic mutations of NOX2, p22phox or EROS contribute to a rare immunodeficiencie named Chronic Granulomatous Disease (CGD), and may pave the way for improved diagnostic strategies and therapeutic approaches.
Recent observations also suggest that EROS may influence how efficiently the NADPH oxidase produces ROS. The precise mechanisms underlying this regulatory process, including how EROS associates with and subsequently dissociates from the complex remain to be elucidated. Furthermore, EROS might play its chaperone role with other isoforms of NOX enzymes (NOX1 and NOX4) and thus could be involved in other pathological processes contributing to Inflammatory Bowel Disease (IBD) or Cancer.
Molecular Views into the Synthesis and Activation of Flavocytochrome b558 in Phagocytic Cells—Focus on the Role of EROS. Rochas P, Val-Pevida M, Beaumel S, Petit-Härtlein I, Plazy C, Fieschi F, Stasia MJ. 202. Antioxidants 15(6):724.
Contact :MJ. Stasia, Membrane and Pathogens Group (IBS/M&P)