Roles of N-glycosylation and lipidation in Wg secretion and signaling.
Roles of N-glycosylation and lipidation in Wg secretion and signaling.
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DOI：
10.1016/j.ydbio.2012.01.009
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发表时间：
2012-04-01
影响因子：
2.7
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Tang X;Wu Y;Belenkaya TY;Huang Q;Ray L;Qu J;Lin X
Wnt成员作为胚胎形成和成体体内平衡所必需的形态发生素。目前，Wnt的分泌及其梯度形成是如何被调控的还不清楚。在这项研究中，我们研究了N-糖基化和脂化/酰化在调节果蝇Wnt主要成员Wingless（Wg）活性中的作用。我们发现，Wg突变体缺乏所有的N-糖基化表现出没有重大缺陷，无论是分泌或信号，表明N-糖基化是Wg活动的缺陷。我们证明，在丝氨酸239（S239），而不是在半胱氨酸93（C93）的脂质修饰起着更重要的作用，在多种发育环境中调节Wg信号。Wg S239突变体与果蝇Frizzled 2（dFz 2）受体结合能力降低，表明S239参与了Wg/受体复合物的形成。重要的是，虽然可以分泌单个Wg C93或Wg S239突变体，但去除C93和S239处的酰基使得Wg不能到达质膜进行分泌。这些数据表明，在C93和S239的脂质修饰在Wg分泌中起主要作用。进一步的实验表明，Wg蛋白中的两个酰基连接位点是Wg与Wnt less（Wls，也称为Evi或Srt）相互作用所必需的，Wnt less是参与Wg分泌的关键货物蛋白。总之，我们的数据证明了在Wg分泌和信号传导中N-糖基化和脂质修饰的体内作用。
Wnt members act as morphogens essential for embryonic patterning and adult homeostasis. Currently, it is still unclear how Wnt secretion and its gradient formation are regulated. In this study, we examined the roles of N-glycosylation and lipidation/acylation in regulating the activities of Wingless (Wg), the main Drosophila Wnt member. We show that Wg mutant devoid of all the N-glycosylations exhibits no major defects in either secretion or signaling, indicating that N-glycosylation is dispensable for Wg activities. We demonstrate that lipid modifications at Serine 239 (S239) rather than that at Cysteine 93 (C93) plays a more important role in regulating Wg signaling in multiple developmental contexts. Wg S239 mutant exhibits a reduced ability to bind its receptor, Drosophila Frizzled 2 (dFz2), suggesting that S239 is involved in the formation of a Wg/receptor complex. Importantly, while single Wg C93 or Wg S239 mutants can be secreted, removal of both acyl groups at C93 and S239 renders Wg incapable of reaching the plasma membrane for secretion. These data argue that lipid modifications at C93 and S239 play major roles in Wg secretion. Further experiments demonstrate that two acyl attachment sites in the Wg protein are required for the interaction of Wg with Wntless (Wls, also known as Evi or Srt), the key cargo protein involved in Wg secretion. Together, our data demonstrate the in vivo roles of N-glycosylation and lipid modification in Wg secretion and signaling.
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