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NADPH oxidase family proteins: signaling dynamics to disease management

Abstract

Reactive oxygen species (ROS) are pervasive signaling molecules in biological systems. In humans, a lack of ROS causes chronic and extreme bacterial infections, while uncontrolled release of these factors causes pathologies due to excessive inflammation. Professional phagocytes such as neutrophils (PMNs), eosinophils, monocytes, and macrophages use superoxide-generating NADPH oxidase (NOX) as part of their arsenal of antimicrobial mechanisms to produce high levels of ROS. NOX is a multisubunit enzyme complex composed of five essential subunits, two of which are localized in the membrane, while three are localized in the cytosol. In resting phagocytes, the oxidase complex is unassembled and inactive; however, it becomes activated after cytosolic components translocate to the membrane and are assembled into a functional oxidase. The NOX isoforms play a variety of roles in cellular differentiation, development, proliferation, apoptosis, cytoskeletal control, migration, and contraction. Recent studies have identified NOX as a major contributor to disease pathologies, resulting in a shift in focus on inhibiting the formation of potentially harmful free radicals. Therefore, a better understanding of the molecular mechanisms and the transduction pathways involved in NOX-mediated signaling is essential for the development of new therapeutic agents that minimize the hyperproduction of ROS. The current review provides a thorough overview of the various NOX enzymes and their roles in disease pathophysiology, highlights pharmacological strategies, and discusses the importance of computational modeling for future NOX-related studies.

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Acknowledgements

This work was supported by the Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI- 123253_YCSA_Faculty) and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers 5P20 GM103424-18 and 3 P20 GM103424-15S1.

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Correspondence to Sanjay Batra.

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Begum, R., Thota, S., Abdulkadir, A. et al. NADPH oxidase family proteins: signaling dynamics to disease management. Cell Mol Immunol 19, 660–686 (2022). https://doi.org/10.1038/s41423-022-00858-1

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  • DOI: https://doi.org/10.1038/s41423-022-00858-1

Keywords

  • NADPH oxidase
  • Reactive oxygen species
  • Inflammation
  • Inhibitors
  • In silico

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