Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes.
Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes.
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DOI：
10.1091/mbc.e12-11-0789
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发表时间：
2013-06
影响因子：
3.3
通讯作者：
Grinstein S
中科院分区：
文献类型：
--
作者：
Bohdanowicz M;Schlam D;Hermansson M;Rizzuti D;Fairn GD;Ueyama T;Somerharju P;Du G;Grinstein S
当吞噬细胞探测环境并摄取抗原时，它们会自发地起皱。这些细胞独特地富含磷脂酸，这是皱褶和巨胞饮所必需的。巨噬细胞和树突状细胞不断地观察它们的环境，寻找外来颗粒和可溶性抗原。这种监视涉及到不断延伸的肌动蛋白丰富的突起和随之而来的吞噬体和巨胞饮体的形成。诱导这种组成性细胞骨架重塑的信号尚未确定。我们报告说，与非吞噬细胞，巨噬细胞和未成熟的树突状细胞有磷脂酸（PA）在其质膜水平升高。质膜PA由甘油二酯磷酸化合成，甘油二酯又由G蛋白刺激的磷脂酶C产生。二酰基甘油激酶活性的抑制导致T细胞淋巴瘤侵袭和转移诱导蛋白1（TIAM 1）--一种Rac鸟嘌呤交换因子--从质膜脱离，从而抑制Rac活性并废除表征巨噬细胞和未成熟树突状细胞的组成性皱褶和巨胞饮。PA的积累和TIAM 1与膜的结合需要磷脂酰肌醇-4，5-二磷酸3-激酶的活性。因此，PA生物合成的独特的组成性途径促进免疫监视所需的肌动蛋白重塑。
Phagocytes spontaneously ruffle as they probe their environment and take up antigens. These cells are uniquely enriched in phosphatidic acid, which is necessary for ruffling and macropinocytosis. Macrophages and dendritic cells continuously survey their environment in search of foreign particles and soluble antigens. Such surveillance involves the ongoing extension of actin-rich protrusions and the consequent formation of phagosomes and macropinosomes. The signals inducing this constitutive cytoskeletal remodeling have not been defined. We report that, unlike nonphagocytic cells, macrophages and immature dendritic cells have elevated levels of phosphatidic acid (PA) in their plasma membrane. The plasmalemmal PA is synthesized by phosphorylation of diacylglycerol, which is in turn generated by a G protein–stimulated phospholipase C. Inhibition of diacylglycerol kinase activity results in the detachment of T-cell lymphoma invasion and metastasis–inducing protein 1 (TIAM1)—a Rac guanine exchange factor—from the plasma membrane, thereby depressing Rac activity and abolishing the constitutive ruffling and macropinocytosis that characterize macrophages and immature dendritic cells. Accumulation of PA and binding of TIAM1 to the membrane require the activity of phosphatidylinositol-4,5-bisphosphate 3-kinase. Thus a distinctive, constitutive pathway of PA biosynthesis promotes the actin remodeling required for immune surveillance.