Rac-dependent feedforward autoactivation of NOX2 leads to oxidative burst.
Rac-dependent feedforward autoactivation of NOX2 leads to oxidative burst.
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DOI：
10.1016/j.jbc.2021.100982
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Heo J
中科院分区：
文献类型：
--
作者：
Hoang HM;Johnson HE;Heo J
NADPH氧化酶2 （NOX2）产生超氧阴离子自由基（O2−），在细胞信号传导和免疫防御中都有作用。NOX2是一种多聚体蛋白复合物，由包括GTPase Rac在内的几个蛋白质亚基组成。NOX2独特地促进了氧化爆发，其描述为最初缓慢的O2−产生，随着时间的推移而增加。NOX2氧化爆发被认为对免疫防御至关重要，因为它可以加速O2−的产生，以应对感染。然而，这种氧化爆发的发生和发展机制及其对NOX2调控的影响尚不清楚。在这项研究中，我们发现NOX2氧化爆发是NOX2自激活与Rac氧化还原功能耦合的结果。当活性Rac触发NOX2激活并随后产生O2−时，NOX2自激活开始，O2−反过来激活氧化还原敏感的Rac。激活的Rac进一步激活NOX2，放大前馈循环，导致NOX2介导的氧化爆发。通过基于诱变的动力学和细胞分析，我们发现Rac的酶促激活完全负责产生激活NOX2自激活的Rac触发器，而氧化还原介导的Rac激活是NOX2自激活的主要驱动力，并有助于细胞中产生约98%的活性NOX2。本研究的结果提供了对NOX2功能调控的深入了解，可用于开发治疗方法来控制与失调的NOX2氧化爆发相关的免疫反应。
NADPH oxidase 2 (NOX2) produces the superoxide anion radical (O2−), which has functions in both cell signaling and immune defense. NOX2 is a multimeric-protein complex consisting of several protein subunits including the GTPase Rac. NOX2 uniquely facilitates an oxidative burst, which is described by initially slow O2− production, which increases over time. The NOX2 oxidative burst is considered critical to immune defense because it enables expedited O2− production in response to infections. However, the mechanism of the initiation and progression of this oxidative burst and its implications for regulation of NOX2 have not been clarified. In this study, we show that the NOX2 oxidative burst is a result of autoactivation of NOX2 coupled with the redox function of Rac. NOX2 autoactivation begins when active Rac triggers NOX2 activation and the subsequent production of O2−, which in turn activates redox-sensitive Rac. This activated Rac further activates NOX2, amplifying the feedforward cycle and resulting in a NOX2-mediated oxidative burst. Using mutagenesis-based kinetic and cell analyses, we show that enzymatic activation of Rac is exclusively responsible for production of the active Rac trigger that initiates NOX2 autoactivation, whereas redox-mediated Rac activation is the main driving force of NOX2 autoactivation and contributes to generation of ∼98% of the active NOX2 in cells. The results of this study provide insight into the regulation of NOX2 function, which could be used to develop therapeutics to control immune responses associated with dysregulated NOX2 oxidative bursts.
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影响因子：
15.9
作者：
DINAUER, MC;PIERCE, EA;ORKIN, SH
通讯作者：
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发表时间：
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期刊：
Antioxidants (Basel, Switzerland)
影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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