The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway
The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway
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DOI：
10.1091/mbc.e07-06-0594
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Confalonieri, Stefano
中科院分区：
文献类型：
--
作者：
Frittoli, Emanuela;Palamidessi, Andrea;Confalonieri, Stefano
在整个进化过程中，新基因和蛋白质的产生被认为是全基因组和基因复制、外显子重排以及逆转座事件的结果。因此，对这类基因的分析可能有助于揭示与高度进化物种相关的功能复杂性。TBC1D3就是这样一个例子，它是灵长类动物特有的基因，含有一个TBC结构域。由于TBC结构域编码Rab特异性GAP活性，因此含有TBC的蛋白质预计在内吞作用和细胞内运输中发挥重要作用。在此，我们表明TBC1D3基因在进化后期产生，很可能是通过RNTRE基因座的复制，并在灵长类物种形成过程中经历了基因扩增。尽管TBC1D3拥有TBC结构域，但它显然缺乏Rab - GAP活性。然而，TBC1D3通过参与一条涉及ARF6和RAB5的新途径，调节表皮生长因子介导的巨胞饮作用的最佳速率。此外，TBC1D3以ARF6依赖的方式与ARF6效应蛋白GGA3结合并共定位，并与之协同促进巨胞饮作用，这表明这两种蛋白质在该过程中共同发挥作用。相应地，GGA3 siRNA介导的敲除会损害TBC1D3诱导的巨胞饮作用。因此，我们发现了一条在灵长类物种形成后出现的新信号通路。在这条通路中，TBC1D3:GGA3复合物有助于信号的最佳传递，最终促进巨胞饮过程。
The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primate-specific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor-mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3: GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process.