The phagocyte NADPH oxidase depends on cholesterol-enriched membrane microdomains for assembly

We propose that lipid rafts function in the recruitment and spatial orientation of cytosolic phox proteins in relation to cyto b558

Frederik Vilhardt; Bo van Deurs

2004

Scholarcy highlights

  • The superoxide-producing phagocyte NADPH oxidase plays an instrumental role in host defense
  • We here show that NADPH oxidase subunits in a cholesterol-dependent fashion are included in low-density detergent-resistant membrane indicative of raft localization and, further, that superoxide production is inhibited by cholesterol depletion due to impaired translocation of cytosolic phox protein subunits to the membrane
  • While the role of rafts as signaling platforms in the organization of components in membrane-directed intracellular signaling is widely accepted, the phagocyte NADPH oxidase represents one of the first macromolecular enzymatic complexes, which depends on biological rafts for dynamic assembly and enzymatic function
  • For example, ion channels and membrane receptors, have been identified in low-density DRM or rafts, but in these instances assembly of the holoenzyme is permanent, unlike the situation for the phagocyte NADPH oxidase, which dynamically assembles on rafts in response to external stimuli
  • While this article was under revision, Dekker and coworkers found the efficiency of neutrophil NADPH oxidase activity to depend on lipid rafts
  • In contrast to our results, mbCD-mediated extraction of cholesterol in neutrophils did not cause a reduction in the magnitude of superoxide release, but rather caused a lag phase before the onset of superoxide production
  • Our in vitro data from the cell-free reconstituted assay demonstrate that raft disruption by cholesterol extraction has a direct negative effect on NADPH oxidase assembly and superoxide generation

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