Patched, the receptor of Hedgehog, is a lipoprotein receptor
Patched, the receptor of Hedgehog, is a lipoprotein receptor
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DOI：
10.1073/pnas.0705603105
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发表时间：
2008-01-22
影响因子：
11.1
通讯作者：
Guerrero, Isabel
中科院分区：
文献类型：
--
作者：
Callejo, Ainhoa;Culi, Joaquim;Guerrero, Isabel
Hedgehog (Hh) 分泌信号蛋白家族在后生动物发育过程中具有广泛的功能，并对人类疾病产生影响。尽管 Hh 被两种亲脂性加合物修饰，但 Hh 会迁移到远离其合成位点的位置，并根据其局部浓度来编程细胞结果。最近，脂蛋白被认为可以作为载体介导果蝇中的 Hh 转运。在这里，我们研究了脂蛋白 (Lp)（果蝇脂蛋白）在翼成虫盘 Hh 信号传导中的作用，翼成虫盘是一种不表达 Lp 但通过血淋巴获取 Lp 的组织。我们利用 Lp 受体 2 (LpR2)（在成虫盘细胞中表达的主要 Lp 受体）的上调来增加 Lp 内吞作用，并局部减少翼盘上皮中可用的游离细胞外 Lp 的量。在这种情况下，分泌的Hh在细胞外基质中不稳定。在普遍降低血淋巴 Lp 水平后，我们获得了类似的结果。这些数据表明，Hh 必须与 Lp 一起包装在生产细胞中才能正确传播。有趣的是，我们还表明，Hh 受体 Patched (Ptc) 是一种脂蛋白受体； Ptc 以不依赖 Hh 的方式主动将 Lp 内化到内吞区室中，并与 Lp 发生物理相互作用。 Ptc作为脂蛋白受体，可以影响成虫盘细胞的细胞内脂质稳态。然而，通过使用不同的 Ptc 突变体，我们表明 Lp 内化在 Hh 信号转导中不起主要作用，但在 Hh 梯度形成中起主要作用。
The Hedgehog (Hh) family of secreted signaling proteins has a broad variety of functions during metazoan development and implications in human disease. Despite Hh being modified by two lipophilic adducts, Hh migrates far from its site of synthesis and programs cellular outcomes depending on its local concentrations. Recently, lipoproteins were suggested to act as carriers to mediate Hh transport in Drosophila. Here, we examine the role of lipophorins (Lp), the Drosophila lipoproteins, in Hh signaling in the wing imaginal disk, a tissue that does not express Lp but obtains it through the hemolymph. We use the up-regulation of the Lp receptor 2 (LpR2), the main Lp receptor expressed in the imaginal disk cells, to increase Lp endocytosis and locally reduce the amount of available free extracellular Lp in the wing disk epithelium. Under this condition, secreted Hh is not stabilized in the extracellular matrix. We obtain similar results after a generalized knock-down of hemolymph Lp levels. These data suggest that Hh must be packaged with Lp in the producing cells for proper spreading. Interestingly, we also show that Patched (Ptc), the Hh receptor, is a lipoprotein receptor; Ptc actively internalizes Lp into the endocytic compartment in a Hh-independent manner and physically interacts with Lp. Ptc, as a lipoprotein receptor, can affect intracellular lipid homeostasis in imaginal disk cells. However, by using different Ptc mutants, we show that Lp internalization does not play a major role in Hh signal transduction but does in Hh gradient formation.