NADPH氧化酶
生物
细胞生物学
信号转导
断点群集区域
酪氨酸磷酸化
磷酸化
基因沉默
蛋白质酪氨酸磷酸酶
活性氧
生物化学
受体
基因
作者
Milena Bertolotti,Giada Farinelli,M Galli,Alessandro Aiuti,Roberto Sitia
标识
DOI:10.1189/jlb.2ab0116-045r
摘要
H2O2 acts as a second messenger in key signaling circuits, transiently modulating tyrosine phosphatases and kinases. We investigated its origin, membrane transport, and functional role during B cell activation and differentiation. Our data identified NADPH-oxidase 2 as the main source of H2O2 and aquaporin 8 as a transport facilitator across the plasma membrane. On aquaporin 8 silencing, inducible B lymphoma cells responded poorly to TLR and BCR stimulation. Their differentiation was severely impaired, as demonstrated by retarded onset of IgM polymerization, low amounts of IgM secretion, and prolonged BCR expression on the cell surface. A silencing-resistant aquaporin 8 rescued responsiveness, confirming that the import of H2O2 across the membrane is essential for B cell activation. The addition of exogenous catalase to primary B splenocytes severely impaired the tyrosine phosphorylation induced by BCR cross-linking, as did the absence of NOX2 in a murine model of chronic granulomatous disease. Importantly, re-expression of gp91phox through gene therapy restored the specific B cell signaling deficiency in NOX2-/- cells. Thus, efficient induction of B cell activation and differentiation requires intact H2O2 fluxes across the plasma membrane for signal amplification.
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