Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase
Unexpected function of the phagocyte NADPH oxidase in supporting hyperglycolysis in stimulated neutrophils: key role of 6-phosphofructo-2-kinase
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DOI：
10.1096/fj.201600720r
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发表时间：
2017-02-01
期刊：
影响因子：
4.8
通讯作者：
Paclet, Marie-Helene
中科院分区：
文献类型：
--
作者：
Baillet, Athan;Hograindleur, Marc-Andre;Paclet, Marie-Helene
吞噬细胞NADPH氧化酶2（Nox 2）是一种酶复合物，参与先天免疫，特别是通过其产生毒性活性氧的能力。最近，蛋白质组学分析的组成型活性的Nox 2复合物，从中性粒细胞组分中分离，突出了6-磷酸果糖-2-激酶（PFK-2）的存在。本研究旨在探讨中性粒细胞中PFK-2与NADPH氧化酶的关系。数据已经强调了在刺激的中性粒细胞中PFK-2的活性磷酸化形式与Nox 2复合物的特异性关联。在其活性形式中，PFK-2催化果糖-2，6-二磷酸的产生，果糖-2，6-二磷酸是糖酵解中的限制酶磷酸果糖-1-激酶的主要变构激活剂。通过小干扰RNA策略对PFK-2磷酸化和PFK-2细胞耗竭的药理学抑制导致糖酵解速率降低和刺激细胞中NADPH氧化酶活性降低。令人惊讶的是，Nox 2活性的改变影响糖酵解速率，这表明中性粒细胞中的Nox 2不仅是活性氧产生所需的，而且还参与支持由炎症条件诱导的能量代谢增加。PFK-2似乎是连接NADPH氧化酶活化和糖酵解调节的策略元件，因此，被提议作为炎性疾病的潜在治疗靶点。
The phagocyte NADPH oxidase 2 (Nox2) is an enzymatic complex that is involved in innate immunity, notably via its capacity to produce toxic reactive oxygen species. Recently, a proteomic analysis of the constitutively active Nox2 complex, isolated from neutrophil fractions, highlighted the presence of 6-phosphofructo-2-kinase (PFK-2). The purpose of this work was to study the relationship between PFK-2 and NADPH oxidase in neutrophils. Data have underlined a specific association of the active phosphorylated form of PFK-2 with Nox2 complex in stimulated neutrophils. In its active form, PFK-2 catalyzes the production of fructose-2,6-bisphosphate, which is the main allosteric activator of phosphofructo-1-kinase, the limiting enzyme in glycolysis. Pharmacologic inhibition of PFK-2 phosphorylation and cell depletion in PFK-2 by a small interfering RNA strategy led to a decrease in the glycolysis rate and a reduction in NADPH oxidase activity in stimulated cells. Surprisingly, alteration of Nox2 activity impacted the glycolysis rate, which indicated that Nox2 in neutrophils was not only required for reactive oxygen species production but was also involved in supporting the energetic metabolism increase that was induced by inflammatory conditions. PFK-2 seems to be a strategic element that links NADPH oxidase activation and glycolysis modulation, and, as such, is proposed as a potential therapeutic target in inflammatory diseases.