atp释放的泛联蛋白通道由溶血磷脂门控。

Erik Henze, Russell N Burkhardt, Bennett W Fox, Tyler J Schwertfeger, Eric Gelsleichter, Kevin Michalski, Lydia Kramer, Margret Lenfest, Jordyn M Boesch, Hening Lin, Frank C Schroeder, Toshimitsu Kawate
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引用次数: 0

摘要

三磷酸腺苷(ATP)作为细胞外信使,介导多种细胞间通讯。令人信服的证据表明,ATP是通过pannexins(一种七聚体大孔形成通道)从细胞中释放出来的。然而,通过泛内联蛋白触发ATP释放的激活机制仍然知之甚少。在这里,我们发现溶血磷脂作为内源性泛联蛋白激活剂,使用小鼠组织提取物的活性引导分离结合非靶向代谢组学和电生理学。我们发现溶血磷脂在没有其他蛋白质的情况下直接和可逆地激活泛内联蛋白。分子对接、诱变和单粒子低温电镜重建表明,溶血磷脂通过改变n端结构域的构象打开泛连接蛋白通道。我们的研究结果提供了脂质代谢和ATP信号之间的联系,两者在炎症和神经传递中都起着重要作用。一句话总结:非靶向代谢组学发现一类信使脂质是炎症和神经传递重要的膜通道的内源性激活剂。
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ATP-release pannexin channels are gated by lysophospholipids.

In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.

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