The nuclear membrane leukotriene synthetic complex is a signal integrator and transducer.
The nuclear membrane leukotriene synthetic complex is a signal integrator and transducer.
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DOI：
10.1091/mbc.e12-06-0489
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发表时间：
2012-11
影响因子：
3.3
通讯作者：
Soberman RJ
中科院分区：
文献类型：
--
作者：
Bair AM;Turman MV;Vaine CA;Panettieri RA Jr;Soberman RJ
白三烯是由花生四烯酸衍生的生物活性信号分子，可启动和放大天然免疫。一个单一的结构，白三烯合成复合体，在中性粒细胞的核膜上整合并传递细胞外信号，产生趋化脂质LTB4。白三烯(LTS)是由花生四烯酸(AA)衍生的脂质信号分子，可启动和放大炎症。为了启动LT的形成，5-脂氧合酶(5-LO)酶转移到核膜上，在那里它与其支架蛋白5-脂氧合酶激活蛋白(FLAP)结合，形成多蛋白LT合成复合体的核心。瓣的功能被认为是通过结合游离AA并促进其作为底物由5-LO形成初始LT，LTA4来实现的。我们使用荧光寿命成像显微镜、细胞生物学和生物化学相结合的方法来鉴定发生在核膜上的离散的AA依赖和AA非依赖的步骤，以控制LT合成复合体在多形核白细胞中的组装。AA与FLAW的结合改变了支架蛋白的构型，促进了膜相关5-LO的募集，与FLAW形成了复合体，并控制了这种结合的紧密程度。粒细胞单核细胞集落刺激因子提供了第二个AA不依赖的信号，该信号控制复合体内5-LO和Flat的紧密程度，但不控制组装的复合体的数量。我们的结果表明，LT合成的复合体是一个信号积分器，它传递细胞外信号来调节5-LO和FLOW的相互作用。
Leukotrienes are bioactive signaling molecules derived from arachidonic acid that initiate and amplify innate immunity. A single structure, the leukotriene synthetic complex, on the nuclear membrane of neutrophils integrates and transduces extracellular signals to generate the chemotactic lipid LTB4. Leukotrienes (LTs) are lipid-signaling molecules derived from arachidonic acid (AA) that initiate and amplify inflammation. To initiate LT formation, the 5-lipoxygenase (5-LO) enzyme translocates to nuclear membranes, where it associates with its scaffold protein, 5-lipoxygenase–activating protein (FLAP), to form the core of the multiprotein LT synthetic complex. FLAP is considered to function by binding free AA and facilitating its use as a substrate by 5-LO to form the initial LT, LTA4. We used a combination of fluorescence lifetime imaging microscopy, cell biology, and biochemistry to identify discrete AA-dependent and AA-independent steps that occur on nuclear membranes to control the assembly of the LT synthetic complex in polymorphonuclear leukocytes. The association of AA with FLAP changes the configuration of the scaffold protein, enhances recruitment of membrane-associated 5-LO to form complexes with FLAP, and controls the closeness of this association. Granulocyte monocyte colony–stimulating factor provides a second AA-independent signal that controls the closeness of 5-LO and FLAP within complexes but not the number of complexes that are assembled. Our results demonstrate that the LT synthetic complex is a signal integrator that transduces extracellular signals to modulate the interaction of 5-LO and FLAP.