Porcupine-mediated lipidation is required for Wnt recognition by Wls
Porcupine-mediated lipidation is required for Wnt recognition by Wls
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DOI：
10.1016/j.ydbio.2011.11.003
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发表时间：
2012-01-15
影响因子：
2.7
通讯作者：
Basler, Konrad
中科院分区：
文献类型：
--
作者：
Herr, Patrick;Basler, Konrad
Wnt蛋白是一个保守的分泌信号配体家族的成员，在发育和组织稳态中起着至关重要的作用。越来越多的证据表明，异常的Wnt产生是Wnt信号转导失调的根本原因，但对这一过程知之甚少。已知在分泌中起作用的一种蛋白质是跨膜蛋白Wntless（Wls）。然而，Wls促进Wnt分泌的机制是一个谜。目前尚不清楚哪些Wnt家族成员需要Wls，以及使它们中的一些依赖Wls分泌的结构要求是什么。在这里，我们提出了一个系统的分析，所有已知的果蝇Wnt家族成员就其依赖WLS功能的分泌。我们首先表明，在保守位点的Wg的糖基化状态并不决定其依赖于WLS。此外，与鼠wls明显相反，果蝇wls不是典型Wnt信号传导的靶基因。然后，我们表明，所有的Wnt，除了WntD，需要WLS的分泌。所有的Wnt，除了WntD，还包含一个保守的丝氨酸残基（在Wg S239），我们证明这是必不可少的功能和物理相互作用与Wls。最后，除了WntD之外，所有的Wnt都需要酰基转移酶Porcupine的活性和与Wls的功能性相互作用。总之，这些发现表明，S239-等效残基的Por-mediated脂质化对于与Wls的相互作用和Wls的分泌是必不可少的。(C)2011 Elsevier Inc. All rights reserved.
Wnt proteins are members of a conserved family of secreted signaling ligands and play crucial roles during development and in tissue homeostasis. There is increasing evidence that aberrant Wnt production is an underlying cause of dysregulated Wnt signaling, however little is known about this process. One protein known to play a role in secretion is the transmembrane protein Wntless (Wls). However, the mechanism by which Wls promotes Wnt secretion is a riddle. It is not known which Wnt family members require Wls and what the structural requirements are that make some of them reliant on Wls for secretion. Here we present a systematic analysis of all known Drosophila Wnt family members with respect to their dependence on Wls function for secretion. We first show that the glycosylation status of Wg at conserved sites does not determine its dependence on Wls. Moreover, in apparent contrast to murine wls, Drosophila wls is not a target gene of canonical Wnt signaling. We then show that all Wnts, with the exception of WntD, require Wls for secretion. All Wnts, with the exception of WntD, also contain a conserved Serine residue (in Wg S239), which we show to be essential for their functional and physical interaction with Wls. Finally, all Wnts, with the exception of WntD, require the acyltransferase Porcupine for activity and for functionally interacting with Wls. Together, these findings indicate that Por-mediated lipidation of the S239-equivalent residue is essential for the interaction with, and secretion by, Wls. (C) 2011 Elsevier Inc. All rights reserved.