TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia
TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia
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DOI：
10.1101/gad.1966210
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发表时间：
2010-10-01
影响因子：
10.5
通讯作者：
Jackson, Peter K.
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Saikat;Wen, Xiaohui;Jackson, Peter K.
初级纤毛在从哺乳动物Hedgehog信号到神经元控制肥胖的一系列过程中起着感觉信号隔间的作用。鞭毛内转运(IFT)是一种古老的、保守的机制，需要组装纤毛和纤毛内运输。IFT、感觉信号和肥胖之间的联系没有明确的定义，但一些新的单基因肥胖症可能与纤毛缺陷有关。这只胖乎乎的小鼠是由Tub基因突变引起的，表现为成年后出现肥胖症。这些筒状蛋白包括一个相关的、知之甚少的蛋白家族，它们在神经发育和功能中扮演着重要角色。我们发现特定的Tubby家族蛋白，特别是Tubby样蛋白3(TULP3)与IFT-A复合体结合。IFT-A与逆行纤毛运输有关，但令人惊讶的是，我们发现IFT-A复合体还有第二个角色，指导TULP3的纤毛进入。TULP3和IFT-A反过来促进G蛋白偶联受体(GPCRs)的子集运输到纤毛，但不是平滑的。睫状肌GPCR定位需要TULP3的IFT-A和膜磷脂酰肌醇结合特性。TULP3和IFT-A蛋白都负向调节小鼠胚胎中的Hedgehog信号，TULP3和IFT-A的相互作用表明了这些蛋白质在神经管模式形成过程中是如何合作的。
Primary cilia function as a sensory signaling compartment in processes ranging from mammalian Hedgehog signaling to neuronal control of obesity. Intraflagellar transport (IFT) is an ancient, conserved mechanism required to assemble cilia and for trafficking within cilia. The link between IFT, sensory signaling, and obesity is not clearly defined, but some novel monogenic obesity disorders may be linked to ciliary defects. The tubby mouse, which presents with adult-onset obesity, arises from mutation in the Tub gene. The tubby-like proteins comprise a related family of poorly understood proteins with roles in neural development and function. We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. TULP3 and IFT-A, in turn, promote trafficking of a subset of G protein-coupled receptors (GPCRs), but not Smoothened, to cilia. Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3-IFT-A interaction suggests how these proteins cooperate during neural tube patterning.