Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.
Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.
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DOI：
10.1016/j.celrep.2012.07.010
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发表时间：
2012-08-30
期刊：
影响因子：
8.8
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Tukachinsky H;Kuzmickas RP;Jao CY;Liu J;Salic A
Hedgehog 信号通路在后生动物发育和癌症中发挥着关键作用。鉴于刺猬配体被疏水性胆固醇分子共价修饰，使其粘附在细胞膜上，目前尚不清楚刺猬配体如何分泌并扩散到远处的细胞。我们证明，脊椎动物细胞中 Hedgehog 配体的分泌是通过两种不同且协同的胆固醇依赖性结合事件来完成的，一种是由膜蛋白 Dispatched 介导的，另一种是由 Scube 家族成员介导的，后者是斑马鱼中 Hedgehog 信号转导所必需的分泌蛋白。胆固醇修饰足以使异源蛋白与 Scube 相互作用，并以 Scube 依赖性方式分泌。 Dispatched 和 Scube 识别胆固醇的不同结构，类似于尼曼匹克疾病蛋白 1 和 2 与胆固醇相互作用的方式，这表明将 Hedgehog 从 Dispatched 转移到 Scube 的交接机制。因此，Dispatched 和 Scube 合作显着增强胆固醇修饰的 Hedgehog 配体的分泌和溶解度。
The Hedgehog signaling pathway plays critical roles in metazoan development and in cancer. How the Hedgehog ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hedgehog ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, one mediated by the membrane protein Dispatched and the other by a Scube family member, secreted proteins essential for Hedgehog signaling in zebrafish. Cholesterol modification is sufficient for a heterologous protein to interact with Scube, and to be secreted in a Scube-dependent manner. Dispatched and Scube recognize different structural aspects of cholesterol, similar to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hedgehog from Dispatched to Scube. Thus, Dispatched and Scube cooperate to dramatically enhance secretion and solubility of the cholesterol-modified Hedgehog ligand.
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