Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt
Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt
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DOI：
10.1038/emboj.2010.100
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发表时间：
2010-07-07
期刊：
影响因子：
11.4
通讯作者：
Goto, Satoshi
中科院分区：
文献类型：
--
作者：
Mukai, Akiko;Yamamoto-Hino, Miki;Goto, Satoshi
Wingless (Wg)/Wnt 已被提议根据其信号传导水平发挥作为形态发生素的各种功能。因此，不仅 Wg/Wnt 的浓度，而且 Wg/Wnt 靶细胞对配体的反应性，在控制细胞输出方面必须具有至关重要的功能。在这里，我们发现 Wg/Wnt 受体 Frizzled 的泛素化和去泛素化的平衡决定了哺乳动物细胞和果蝇中对 Wg/Wnt 的细胞反应性，并且 Frizzled 的细胞表面水平受到去泛素化酶 UBPY/泛素特异性蛋白酶 8 (USP8) 的调节。尽管泛素化的卷曲蛋白经历了溶酶体运输和降解，但 UBPY/USP8 依赖性去泛素化导致卷曲蛋白循环到质膜，从而提高其表面水平。重要的是，UBPY/USP8 功能的增强和丧失分别导致典型 Wg/Wnt 信号传导的上调和下调。这些结果揭示了一种通过控制细胞表面卷曲蛋白水平来调节细胞对 Wg/Wnt 反应性的新机制。 EMBO 杂志 (2010) 29, 2114-2125。 doi：10.1038/emboj.2010.100； 2010 年 5 月 21 日在线发布
Wingless (Wg)/Wnt has been proposed to exert various functions as a morphogen depending on the levels of its signalling. Therefore, not just the concentration of Wg/Wnt, but also the responsiveness of Wg/Wnt-target cells to the ligand, must have a crucial function in controlling cellular outputs. Here, we show that a balance of ubiquitylation and deubiquitylation of the Wg/Wnt receptor Frizzled determines the cellular responsiveness to Wg/Wnt both in mammalian cells and in Drosophila, and that the cell surface level of Frizzled is regulated by deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8). Although ubiquitylated Frizzled underwent lysosomal trafficking and degradation, UBPY/USP8-dependent deubiquitylation led to recycling of Frizzled to the plasma membrane, thereby elevating its surface level. Importantly, a gain and loss of UBPY/USP8 function led to up-and down-regulation, respectively, of canonical Wg/Wnt signalling. These results unveil a novel mechanism that regulates the cellular responsiveness to Wg/Wnt by controlling the cell surface level of Frizzled. The EMBO Journal (2010) 29, 2114-2125. doi:10.1038/emboj.2010.100; Published online 21 May 2010