The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling.
The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling.
复制标题
DOI：
10.1126/scisignal.2000976
复制
发表时间：
2010-08-03
影响因子：
7.3
通讯作者：
Williams MS
中科院分区：
文献类型：
--
作者：
Kwon J;Shatynski KE;Chen H;Morand S;de Deken X;Miot F;Leto TL;Williams MS
通常通过NADPH（还原形式的烟酰胺腺嘌呤二核苷酸磷酸）氧化酶产生的活性氧物质在细胞对许多受体刺激的信号应答中起作用。在这里，我们描述了钙依赖性，非吞噬NADPH氧化酶Duox 1在原代人CD 4 + T细胞和培养的T细胞系的功能。Duox 1与肌醇1，4，5-三磷酸受体1结合，并且是早期T细胞受体（TCR）刺激的过氧化氢（H2 O2）通过依赖于TCR近端激酶的途径产生所必需的。Duox 1的瞬时或稳定敲除抑制TCR信号传导，特别是70千道尔顿的β链相关蛋白激酶（ZAP-70）的酪氨酸-319的磷酸化，钙离子（Ca 2+）的储存操作进入，以及细胞外信号调节激酶的激活。细胞因子的产生也被Duox 1的敲低抑制。Duox 1介导的含Src同源2结构域的蛋白酪氨酸磷酸酶2的失活促进了ZAP-70的磷酸化及其与Src家族酪氨酸激酶Lck和TCR复合物的CD 3 β链的结合。因此，我们认为，Duox 1的激活，下游的近端TCR信号，产生H2 O2，在一个积极的反馈回路，以增强和维持进一步的TCR信号。
Production of reactive oxygen species, often by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, plays a role in the signaling responses of cells to many receptor stimuli. Here, we describe the function of the calcium-dependent, nonphagocytic NADPH oxidase Duox1 in primary human CD4+ T cells and cultured T cell lines. Duox1 bound to inositol 1,4,5-trisphosphate receptor 1 and was required for early T cell receptor (TCR)–stimulated production of hydrogen peroxide (H2O2) through a pathway that was dependent on TCR-proximal kinases. Transient or stable knockdown of Duox1 inhibited TCR signaling, especially phosphorylation of tyrosine-319 of ζ chain–associated protein kinase of 70 kilodaltons (ZAP-70), store-operated entry of calcium ions (Ca2+), and activation of extracellular signal–regulated kinase. The production of cytokines was also inhibited by knockdown of Duox1. Duox1-mediated inactivation of Src homology 2 domain–containing protein tyrosine phosphatase 2 promoted the phosphorylation of ZAP-70 and its association with the Src family tyrosine kinase Lck and the CD3ζ chain of the TCR complex. Thus, we suggest that activation of Duox1, downstream of proximal TCR signals, generates H2O2 that acts in a positive feedback loop to enhance and sustain further TCR signaling.