Distinct Cation Gradients Power Cholesterol Transport at Different Key Points in the Hedgehog Signaling Pathway.
Distinct Cation Gradients Power Cholesterol Transport at Different Key Points in the Hedgehog Signaling Pathway.
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DOI：
10.1016/j.devcel.2020.08.002
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发表时间：
2020-11-09
影响因子：
11.8
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Petrov K;Wierbowski BM;Liu J;Salic A
胆固醇在Hedgehog信号中扮演着两个关键的角色，Hedgehog信号是动物发育和癌症的基本途径：它共价修饰Sonic Hedgehog(SHH)配体，限制其从产生细胞中释放，并直接激活反应细胞中的Smomoothed。在这两种情况下，与细菌RND转运蛋白相关的膜蛋白调节胆固醇：Dispatched1控制胆固醇基化SHH的释放，Patched1拮抗胆固醇的平滑激活。真核RND蛋白，包括Dispatched1和Patched1，其机制和驱动力尚不清楚。在这里，我们证明了Dispatched1在酶的作用下催化SHH的释放。Dispatched1利用质膜Na+梯度的能量，从而发挥SHH/Na+逆向转运蛋白的作用。相反，Patched1对平滑的抑制需要相反的K+梯度。我们的结果阐明了真核生物必需的RND蛋白的转运蛋白活性，并证明了动物细胞的两个主要阳离子梯度在Hedgehog途径的两个关键步骤中不同地推动胆固醇的运输。Petrov、WierBowski等人的研究成果。研究表明，真核RND蛋白Dispatched1和Patched1是Hedgehog发育信号通路的关键调节因子，它们是由跨质膜的不同离子梯度驱动的转运体：Dispatched1使用Na+催化胆固醇修饰的Sonic Hedgehog分泌，而Patched1使用K+拮抗胆固醇激活的Smomoothed。
Cholesterol plays two critical roles in Hedgehog signaling, a fundamental pathway in animal development and cancer: it covalently modifies the Sonic hedgehog (SHH) ligand, restricting its release from producing cells, and directly activates Smoothened in responding cells. In both contexts, a membrane protein related to bacterial RND transporters regulates cholesterol: Dispatched1 controls release of cholesterylated SHH, and Patched1 antagonizes Smoothened activation by cholesterol. The mechanism and driving force for eukaryotic RND proteins, including Dispatched1 and Patched1, are unknown. Here, we show that Dispatched1 acts enzymatically to catalyze SHH release. Dispatched1 uses the energy of the plasma membrane Na+ gradient, thus functioning as an SHH/Na+ antiporter. In contrast, Patched1 repression of Smoothened requires the opposing K+ gradient. Our results clarify the transporter activity of essential eukaryotic RND proteins, and demonstrate that the two main cation gradients of animal cells differentially power cholesterol transport at two crucial steps in the Hedgehog pathway. Petrov, Wierbowski et al. show that eukaryotic RND proteins Dispatched1 and Patched1, key regulators of the Hedgehog developmental signaling pathway, are transporters powered by distinct ion gradients across the plasma membrane: Dispatched1 uses Na+ to catalyze cholesterol-modified Sonic hedgehog secretion, while Patched1 uses K+ to antagonize Smoothened activation by cholesterol.
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