Patched regulates Smoothened trafficking using lipoprotein-derived lipids
Patched regulates Smoothened trafficking using lipoprotein-derived lipids
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DOI：
10.1242/dev.041392
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发表时间：
2009-12-15
期刊：
影响因子：
4.6
通讯作者：
Eaton, Suzanne
中科院分区：
文献类型：
--
作者：
Khaliullina, Helena;Panakova, Daniela;Eaton, Suzanne
Hedgehog（Hh）是一种脂蛋白携带的配体，其调节多种脊椎动物和无脊椎动物组织中的模式化和增殖。当Hh不存在时，其受体Patched（Ptc）通过与基底外侧膜上Smo水平降低相关的未知催化机制抑制Smoothened（Smo）信号传导。Ptc含有一个甾醇敏感结构域，与Niemann-Pick型C-1蛋白相似，表明Ptc可能通过调节脂质转运来抑制Smo。然而，尚未确定Smo的内源性脂质调节剂，也从未显示Ptc实际上控制脂质运输。在这里，我们表明，果蝇Ptc招聘内化的脂蛋白Ptc阳性内体和它的甾醇敏感域调节贩运的脂质和Smo从这个车厢。Ptc利用来自脂蛋白的脂质使基底外侧膜上的Smo不稳定。我们建议，铂通常通过改变内体的脂质组成，通过Smo传递调节Smo降解，和Hh的存在下，脂蛋白抑制利用他们的脂质的铂。
Hedgehog (Hh) is a lipoprotein-borne ligand that regulates both patterning and proliferation in a wide variety of vertebrate and invertebrate tissues. When Hh is absent, its receptor Patched (Ptc) represses Smoothened (Smo) signaling by an unknown catalytic mechanism that correlates with reduced Smo levels on the basolateral membrane. Ptc contains a sterol-sensing domain and is similar to the Niemann-Pick type C-1 protein, suggesting that Ptc might regulate lipid trafficking to repress Smo. However, no endogenous lipid regulators of Smo have yet been identified, nor has it ever been shown that Ptc actually controls lipid trafficking. Here, we show that Drosophila Ptc recruits internalized lipoproteins to Ptc-positive endosomes and that its sterol-sensing domain regulates trafficking of both lipids and Smo from this compartment. Ptc utilizes lipids derived from lipoproteins to destabilize Smo on the basolateral membrane. We propose that Ptc normally regulates Smo degradation by changing the lipid composition of endosomes through which Smo passes, and that the presence of Hh on lipoproteins inhibits utilization of their lipids by Ptc.