Abstract
ABSTRACTIn dendritic cells, the NADPH oxidase 2 complex (NOX2) is recruited to the phagosomal membrane during antigen uptake. NOX2 produces reactive oxygen species (ROS) in the lumen of the phagosome that kill ingested pathogens, delay antigen breakdown and alter the peptide repertoire for presentation to T cells. How the integral membrane component of NOX2, cytochrome b558 (which comprises CYBB and CYBA), traffics to phagosomes is incompletely understood. In this study, we show in dendritic cells derived from human blood-isolated monocytes that cytochrome b558 is initially recruited to the phagosome from the plasma membrane during phagosome formation. Cytochrome b558 also traffics from a lysosomal pool to phagosomes and this is required to replenish oxidatively damaged NOX2. We identified syntaxin-7, SNAP23 and VAMP8 as the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediating this process. Our data describe a key mechanism of how dendritic cells sustain ROS production after antigen uptake that is required to initiate T cell responses.
Highlights
Phagocytosis is an essential process by which immune cells clear microbial pathogens as well as apoptotic and necrotic cells
Activation by immune stimuli can result in enrichment of gp91phox on the plasma membrane (Bedard and Krause, 2007; Borregaard et al, 1983), raising the possibility that gp91phox is recruited to nascent phagosomes from the plasma membrane
Around 10% of the total level of gp91phox was present on the plasma membrane in resting dendritic cells, and this percentage increased to approximately 22% after zymosan stimulation (Fig. 1A)
Summary
Phagocytosis is an essential process by which immune cells clear microbial pathogens as well as apoptotic and necrotic (tumor) cells. Both the plasma membrane and intracellular vesicles contribute to phagosome formation, as intracellular vesicles fuse with the plasma membrane at the cup of the nascent phagosome (Canton and Grinstein, 2014; Fairn and Grinstein, 2012; Lu and Zhou, 2012). NOX2 consists of the three cytosolic proteins: p47phox (NCF1), p40phox.
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