SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion.
SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion.
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DOI：
10.1038/s41467-018-06114-3
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发表时间：
2018-09-13
影响因子：
16.6
通讯作者：
Cullen PJ
中科院分区：
文献类型：
--
作者：
McGough IJ;de Groot REA;Jellett AP;Betist MC;Varandas KC;Danson CM;Heesom KJ;Korswagen HC;Cullen PJ
Wntless将Wnt形态发生蛋白转运至细胞表面，并且是Wnt分泌和形态发生梯度形成所需的。内吞的Wntless的再循环需要分选连接蛋白-3（SNX 3）-逆转录依赖性内体-高尔基体转运途径。在这里，我们证明了SNX 3-retromer组装对Wntless运输的重要作用，并报告SNX 3与由MON 2，DOPEY 2和推定的氨基磷脂移位酶ATP 9A组成的进化保守的内体相关膜重建复合物相关。Ce-mon-2、Ce-pad-1或Ce-tat-5（各自的MON 2、DOPEY 2和ATP 9A直系同源物）表型复制的体内抑制导致SNX 3-逆转录功能的丧失，导致Wntless和Wnt表型的溶酶体降解增强。在ATP酶抑制的达特-5（E246 Q）突变体过表达时也观察到扰动的Wnt信号传导，这表明磷脂翻转酶活性在SNX 3逆转录酶介导的Wntless分选过程中的作用。总之，这些发现提供了体外和体内机制的细节，以描述SNX 3-逆转录酶介导的运输过程中Wnt分泌和Wnt形态梯度的形成。持续的Wnt分泌需要内体SNX 3-逆转录复合物用于内化的Wnt伴侣Wntless的内体至反式高尔基体网络转运。在这里，作者表明，在两个C。在线虫和人类细胞中，SNX 3-逆转录聚合物需要进化上保守的膜重塑复合物用于Wnt无分选和Wnt分泌。
Wntless transports Wnt morphogens to the cell surface and is required for Wnt secretion and morphogenic gradients formation. Recycling of endocytosed Wntless requires the sorting nexin-3 (SNX3)-retromer-dependent endosome-to-Golgi transport pathway. Here we demonstrate the essential role of SNX3-retromer assembly for Wntless transport and report that SNX3 associates with an evolutionary conserved endosome-associated membrane re-modelling complex composed of MON2, DOPEY2 and the putative aminophospholipid translocase, ATP9A. In vivo suppression of Ce-mon-2, Ce-pad-1 or Ce-tat-5 (respective MON2, DOPEY2 and ATP9A orthologues) phenocopy a loss of SNX3-retromer function, leading to enhanced lysosomal degradation of Wntless and a Wnt phenotype. Perturbed Wnt signalling is also observed upon overexpression of an ATPase-inhibited TAT-5(E246Q) mutant, suggesting a role for phospholipid flippase activity during SNX3-retromer-mediated Wntless sorting. Together, these findings provide in vitro and in vivo mechanistic details to describe SNX3-retromer-mediated transport during Wnt secretion and the formation of Wnt-morphogenic gradients. Sustained Wnt secretion requires the endosomal SNX3-retromer complex for endosome-to-trans-Golgi network transport of the internalised Wnt chaperone Wntless. Here the authors show that in both C. elegans and human cells, SNX3-retromer requires an evolutionary conserved membrane remodelling complex for Wntless sorting and Wnt secretion.
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影响因子：
3.3
作者：
Hua, ZL;Graham, TR
通讯作者：
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影响因子：
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通讯作者：
Cullen, PJ
DOI：
10.1073/pnas.1410552111
发表时间：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1319947111
发表时间：
2014-02-18
影响因子：
11.1
作者：
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通讯作者：
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