Cholesterol accessibility at the ciliary membrane controls hedgehog signaling
Cholesterol accessibility at the ciliary membrane controls hedgehog signaling
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DOI：
10.7554/elife.50051
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发表时间：
2019-10-30
期刊：
影响因子：
7.7
通讯作者：
Rohatgi, Rajat
中科院分区：
文献类型：
--
作者：
Kinnebrew, Maia;Iverson, Ellen J.;Rohatgi, Rajat
先前我们提出，通过Smoothened的hedgehog信号穿过质膜的传输是由其与胆固醇的相互作用触发的（Luchetti等人，2016年）。但是，胆固醇是一种丰富的脂质，是如何受到足够严格的调节来控制可能导致出生缺陷和癌症的信号系统的呢？使用基于毒素的传感器区分不同的胆固醇池，我们发现Smoothened激活和Hedgehog信号是由生物化学定义的小部分膜胆固醇驱动的，称为可接近胆固醇。通过消耗鞘磷脂增加胆固醇的可及性，鞘磷脂将胆固醇螯合在复合物中，放大了Hedgehog信号传导。Hedgehog配体通过使转运蛋白样蛋白Patched 1失活来增加初级纤毛膜中的胆固醇可及性。捕获这种可接近的胆固醇阻断了Hedgehog信号穿过膜的传递。我们的工作表明，胆固醇在睫状体膜的组织可以被细胞外配体修饰，以控制纤毛定位的信号蛋白的活性。
Previously we proposed that transmission of the hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. Trapping this accessible cholesterol blocks Hedgehog signal transmission across the membrane. Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins.