S100A8:S100A9:AA:Ca(2+) binds NOX2 complex

Stable Identifier
Reaction [binding]
Homo sapiens
Calprotectin heterotetramer binds NOX2 complex
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Ca(2+) flux across the phagosomal membrane influences NADPH oxidase activity and ROS production. Phagocytic engagement of Fc gamma receptor (FcγR) or complement receptor 3 (CR3) activate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), leading to the formation of PI(3,4,5)P3. This phospholipid participates in the activation of phospholipase γ C (PLCγ) and phospholipase D (PLD)-mediated downstream signaling pathways. The generation of IP3 by PLCγ triggers Ca(2+) release from intracellular stores (endoplasmic reticulum, ER) via the opening of IP3 receptors (IP3-R). PLD is involved in the process of sphingosine kinase-produced sphingosine 1-phosphate (S1P), leading to the depletion of intracellular Ca(2+) stores. The emptying of intracellular Ca2+ stores induces the activation of the Ca(2+) sensor stromal interaction molecule-1 (STIM1), which, in turn, activates calcium release-activated calcium channel protein 1 (ORAI1) at the plasma membrane and extracellular Ca(2+) entry. The resulting elevation of Ca(2+) mediates the recruitment of the cytosolic Ca(2+)-activated regulators S100A8 (also know as migration inhibitory factor-related proteins 8 (MRP8)) and S100A9 (MRP14) to the phagosomal membrane (Berthier S et al. 2003, 2012; Steinckwich N et al. 2011; Bréchard S et al. 2013). The translocation of S100A8:S100A9 allows the transfer of S100A9-binding arachidonic acid (AA) to cytochrome b558, favoring the conformational change of cytochrome b558 and promoting intraphagosomal NADPH oxidase activation and ROS production (Berthier S et al. 2003, 2012; Doussiere J et L. 2002; Kerkhoff C et al. 2005; Steinckwich N et al. 2011; Bréchard S et al. 2013 ). S100A8 & S100A9 exist mainly as a S100A8:S100A9 heterodimer which is termed calprotectin based on its role in innate immunity (Korndorfer IP et al. 2007). Ca(2+) is also known to stimulate formation of higher order oligomers of S100 proteins, including S100A8/S100A9 tetramers (Leukert N et al. 2006; Korndörfer IP et al. 2007). In addition, calprotectin has been shown to inhibit bacterial growth through chelation of extracellular manganese Mn(2+), zinc Zn(2+) and possibly iron Fe(2+) and thus restricting metal-ion availability during infection (Damo SM et al. 2013; Hayden JA et al. 2013; Brophy MB et al. 2013; Gagnon DM et al. 2015).

Literature References
PubMed ID Title Journal Year
22808130 Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation

Berthier, S, Nguyen, MV, Morel, F, Polack, B, Paclet, MH, Hograindleur, MA, Baillet, A

PLoS ONE 2012
21239714 An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity

Schenten, V, Bréchard, S, Melchior, C, Steinckwich, N, Tschirhart, EJ

J. Immunol. 2011
23980663 Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis

Nunes, P, Dinauer, MC, Demaurex, N

Traffic 2013
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