Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation.
Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation.
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DOI：
10.1016/j.ydbio.2011.09.001
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发表时间：
2011-12-01
影响因子：
2.7
通讯作者：
Yoder BK
中科院分区：
文献类型：
--
作者：
Berbari NF;Kin NW;Sharma N;Michaud EJ;Kesterson RA;Yoder BK
肿瘤坏死因子α受体3相互作用蛋白1（Traf 3 ip 1），也称为MIPT 3，最初通过其与微管蛋白、肌动蛋白、TNFR相关因子-3（Traf 3）、IL-13 R1和DISC 1的相互作用来表征。它作为IL-13介导的Stat 6磷酸化的抑制剂发挥作用，并将Traf 3和DISC 1螯合到细胞骨架上。对C. elegans（DYF-11）、斑马鱼（elipsa）和衣原体（IFFT 54）的研究表明，该蛋白定位于纤毛，并且是纤毛发生所需的。类似的本地化数据，现在已经报道了哺乳动物Traf 3 ip 1。这提出了一种可能性，即Traf 3 ip 1在哺乳动物纤毛发生中具有进化保守的作用，除了其先前指出的功能。为了评估这种可能性，产生Traf 3 ip 1突变小鼠系。traf 3 ip 1突变细胞不能形成纤毛。纯合子Traf 3 ip 1突变小鼠不能存活，并且具有神经发育缺陷和多指（趾）畸形，这是具有纤毛装配缺陷的小鼠突变体的典型表型。此外，在Traf 3 ip 1突变体中，刺猬通路被破坏，这可以通过异常的背腹神经管模式和刺猬报告基因的表达减少来证明。经典的Wnt途径的分析表明，它在很大程度上不受影响，然而，在咽弓的特定领域有升高水平的报告活性。有趣的是，Traf 3 ip 1突变胚胎和细胞未能显示IL-13信号的改变，这是与其最初发现相关的途径之一。在Traf 3 ip 1突变细胞中观察到的新表型包括乙酰化微管的胞质水平升高和培养中细胞大小的显着增加。扩大Traf 3 ip 1突变体细胞大小与基础mTor通路活性升高相关。两者合计，这些数据表明，Traf 3 ip 1功能是高度保守的纤毛发生，是重要的一些基本的发展和细胞途径的适当调节。Traf 3 ip 1突变小鼠和细胞系将为评估哺乳动物发育中纤毛功能提供有价值的资源，也可作为探索纤毛与细胞骨架动力学、mTor调节和细胞体积控制之间潜在联系的工具。
Tumor necrosis factor alpha receptor 3 interacting protein 1 (Traf3ip1), also known as MIPT3, was initially characterized through its interactions with tubulin, actin, TNFR-associated factor-3 (Traf3), IL-13R1, and DISC1. It functions as an inhibitor of IL-13-mediated phosphorylation of Stat6 and in sequestration of Traf3 and DISC1 to the cytoskeleton. Studies of the Traf3ip1 homologs in C. elegans (DYF-11), Zebrafish (elipsa), and Chlamydomonas (IFT54) revealed that the protein localizes to the cilium and is required for ciliogenesis. Similar localization data has now been reported for mammalian Traf3ip1. This raises the possibility that Traf3ip1 has an evolutionarily conserved role in mammalian ciliogenesis in addition to its previously indicated functions. To evaluate this possibility, a Traf3ip1 mutant mouse line was generated. Traf3ip1mutant cells are unable to form cilia. Homozygous Traf3ip1 mutant mice are not viable and have both neural developmental defects and polydactyly, phenotypes typical of mouse mutants with ciliary assembly defects. Furthermore, in Traf3ip1 mutants the hedgehog pathway is disrupted, as evidenced by abnormal dorsal-ventral neural tube patterning and diminished expression of a hedgehog reporter. Analysis of the canonical Wnt pathway indicates that it was largely unaffected; however, specific domains in the pharyngeal arches have elevated levels of reporter activity. Interestingly, Traf3ip1 mutant embryos and cells failed to show alterations in IL-13 signaling, one of the pathways associated with its initial discovery. Novel phenotypes observed in Traf3ip1 mutant cells include elevated cytosolic levels of acetylated microtubules and a marked increase in cell size in culture. The enlarged Traf3ip1 mutant cell size was associated with elevated basal mTor pathway activity. Taken together, these data demonstrate that Traf3ip1 function is highly conserved in ciliogenesis and is important for proper regulation of a number of essential developmental and cellular pathways. The Traf3ip1 mutant mouse and cell lines will provide valuable resources to assess cilia function in mammalian development and also serve as a tool to explore the potential connections between cilia and cytoskeletal dynamics, mTor regulation, and cell volume control.
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影响因子：
3.5
作者：
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