A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.
A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.
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DOI：
10.1016/j.cell.2015.05.051
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发表时间：
2015-07-02
期刊：
影响因子：
64.5
通讯作者：
Superti-Furga G
中科院分区：
文献类型：
--
作者：
Köberlin MS;Snijder B;Heinz LX;Baumann CL;Fauster A;Vladimer GI;Gavin AC;Superti-Furga G
脂质组成影响细胞膜的生物物理特性，为受体介导的细胞信号传导提供平台。为了研究膜脂组成的调节作用，我们将鞘脂代谢的遗传扰动与toll样受体（TLR）信号传导的不同步骤的定量和基于质谱的脂质组学相结合。膜脂组成受到这些扰动的广泛影响，揭示了一个由协同调节的鞘脂和甘油磷脂组成的圆形网络。这种进化上保守的网络结构同时反映了膜脂代谢、亚细胞定位和适应机制。多种tlr诱导的炎症表型与脂质丰度变化的整合，为整个网络中组织的单个脂质物种赋予了不同的功能作用。这种功能性注释准确地预测了来自脂质储存障碍患者的细胞的炎症反应，仅基于它们改变的膜脂组成。这里描述的分析策略使人们能够理解不同生物系统中膜脂功能的高级组织。脂质网络是保守的，反映了代谢、定位和适应性。鞘脂代谢调节TLR的运输、信号传导、将免疫细胞中的脂质组学与遗传扰动相结合，揭示了脂质间调节结构的逻辑，并使脂质在toll样受体信号传导的不同步骤中的功能分配成为可能。此外，定量脂质组学可以单独预测患者来源细胞的炎症反应。
Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems. Coregulation between membrane lipid species is organized in a circular network The lipid network is conserved and reflects metabolism, localization, and adaptation Sphingolipid metabolism regulates TLR trafficking, signaling, and cytokine release Network-wide functional lipid annotations predict TLR responses in patient cells Combining lipidomics with genetic perturbations in immune cells reveals the logic of inter-lipid regulatory structure and enables the functional assignment of lipids to different steps of Toll-like receptor signaling. Moreover, quantitative lipidomics alone can predict the inflammatory response of patient-derived cells.