Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand.
Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand.
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DOI：
10.1016/j.devcel.2020.09.017
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发表时间：
2020-11-23
影响因子：
11.8
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Wierbowski BM;Petrov K;Aravena L;Gu G;Xu Y;Salic A
Hedgehog信号调控胚胎发生、成体干细胞维持和肿瘤发生中的关键过程。激活配体Sonic hedgehog（SHH）由于双重棕榈酸酯和胆固醇修饰而具有高度疏水性，因此，其从细胞中释放需要分泌的SCUBE蛋白。我们证明，可溶性SCUBE-SHH复合物，虽然在细胞测定中非常有效，但不能直接通过SHH受体Patched 1（PTCH 1）发出信号。相反，SCUBE-SHH的信号传导需要由辅助受体CDON/BOC和GAS 1介导的分子中继，其缓解SCUBE对SHH的抑制。CDON/BOC结合SCUBE和SHH，将复合物募集到细胞表面。然后SHH以双重脂质依赖性方式切换到GAS 1，并从GAS 1切换到PTCH 1，启动信号传导。这些结果定义了刺猬信号传导的一个重要步骤，辅助受体通过将SHH从潜在的细胞外复合物陪伴到其细胞表面受体来激活SHH，并指出辅助受体功能的更广泛范例。Wierbowski等阐明了SHH形态原从产生细胞到应答细胞的穿梭途径。SCUBE释放脂化SHH，但阻止其通过PTCH 1直接信号传导。SCUBE-SHH的信号传导需要辅助受体CDON/BOC和GAS 1，它们将SCUBE-SHH募集到应答细胞并将SHH转移到PTCH 1。
Hedgehog signaling governs critical processes in embryogenesis, adult stem cell maintenance, and tumorigenesis. The activating ligand, Sonic hedgehog (SHH), is highly hydrophobic because of dual palmitate and cholesterol modification, and thus, its release from cells requires the secreted SCUBE proteins. We demonstrate that the soluble SCUBE-SHH complex, although highly potent in cellular assays, cannot directly signal through the SHH receptor, Patched1 (PTCH1). Rather, signaling by SCUBE-SHH requires a molecular relay mediated by the coreceptors CDON/BOC and GAS1, which relieves SHH inhibition by SCUBE. CDON/BOC bind both SCUBE and SHH, recruiting the complex to the cell surface. SHH is then handed off, in a dual lipid-dependent manner, to GAS1, and from GAS1 to PTCH1, initiating signaling. These results define an essential step in Hedgehog signaling, whereby coreceptors activate SHH by chaperoning it from a latent extracellular complex to its cell-surface receptor, and point to a broader paradigm of coreceptor function. Wierbowski et al. elucidate the pathway that shuttles the SHH morphogen from producing to responding cells. SCUBE releases lipidated SHH, but blocks it from directly signaling through PTCH1. Signaling by SCUBE-SHH requires the coreceptors CDON/BOC and GAS1, which recruit SCUBE-SHH to responding cells and transfer SHH to PTCH1.
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