Plasma membrane organization is essential for balancing competing pseudopod- and uropod-promoting signals during neutrophil polarization and migration
Plasma membrane organization is essential for balancing competing pseudopod- and uropod-promoting signals during neutrophil polarization and migration
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DOI：
10.1091/mbc.e05-04-0358
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发表时间：
2005-12-01
影响因子：
3.3
通讯作者：
Welch, MD
中科院分区：
文献类型：
--
作者：
Bodin, S;Welch, MD
中性粒细胞暴露于化学引诱物诱导细胞极化和迁移。这些行为需要不对称激活不同的信号通路和细胞骨架元素在突出的伪足在细胞的前面和收缩尾足在后方。一个重要的悬而未决的问题是，质膜的组织如何参与建立极化和迁移过程中的不对称？为了回答这个问题，我们研究了胆固醇的功能，胆固醇是一种已知会影响膜组织的脂质。通过控制胆固醇消耗，我们发现胆固醇依赖性膜组织通过促进尾足功能和抑制异位伪足形成而使细胞极化和迁移。在机制水平上，我们发现胆固醇是抑制伪足促进G（i）/PI3-激酶信号通路不适当激活的直接必要条件。此外，胆固醇是抑制G（i）依赖性的负反馈RhoA信号通路，从而使RhoA激活和尾足功能。我们的研究结果表明，在一个模型中，胆固醇依赖性膜组织中起着至关重要的作用，在中性粒细胞极化和迁移过程中，通过平衡激活和分离竞争伪足和尾足诱导信号通路的本地化，在建立细胞不对称。
Exposure of neutrophils to chemoattractant induces cell polarization and migration. These behaviors require the asymmetric activation of distinct signaling pathways and cytoskeletal elements in the protruding pseudopod at the front of cells and the retracting uropod at the rear. An important outstanding question is, how does the organization of the plasma membrane participate in establishing asymmetry during polarization and migration? To answer this question, we investigated the function of cholesterol, a lipid known to influence membrane organization. Using controlled cholesterol depletion, we found that a cholesterol-dependent membrane organization enabled cell polarization and migration by promoting uropod function and suppressing ectopic pseudopod formation. At a mechanistic level, we showed that cholesterol was directly required for suppressing inappropriate activation of the pseudopod-promoting G(i)/PI3-kinase signaling pathway. Furthermore, cholesterol was required for dampening G(i)-dependent negative feedback on the RhoA signaling pathway, thus enabling RhoA activation and uropod function. Our findings suggest a model in which a cholesterol-dependent membrane organization plays an essential role in the establishment of cellular asymmetry by balancing the activation and segregating the localization of competing pseudopod- and uropod-inducing signaling pathways during neutrophil polarization and migration.