Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse-108, 01307 Dresden, Germany.
Development. 2009 Dec;136(24):4111-21. doi: 10.1242/dev.041392. Epub 2009 Nov 11.
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.
刺猬 (Hh) 是一种脂蛋白结合配体，可调节多种脊椎动物和无脊椎动物组织的模式形成和增殖。当 Hh 不存在时，其受体 patched (Ptc) 通过一种未知的催化机制抑制 smoothened (Smo) 信号，这种机制与 basolateral 膜上 Smo 水平降低有关。Ptc 含有固醇感应结构域，与尼曼-皮克 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，尚未鉴定出 Smo 的内源性脂质调节剂，也从未证明 Ptc 实际上控制脂质转运。在这里，我们表明果蝇 Ptc 将内化的脂蛋白募集到 Ptc 阳性内体中，其固醇感应结构域调节从该隔室中脂质和 Smo 的转运。Ptc 利用脂蛋白衍生的脂质来破坏 basolateral 膜上的 Smo。我们提出，Ptc 通过改变 Smo 通过的内体的脂质组成来正常调节 Smo 的降解，而脂蛋白上 Hh 的存在抑制了 Ptc 对其脂质的利用。
