SNX-3 mediates retromer-independent tubular endosomal recycling by opposing EEA-1-facilitated trafficking.
SNX-3 mediates retromer-independent tubular endosomal recycling by opposing EEA-1-facilitated trafficking.
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SNX-3 通过对抗 EEA-1 促进的运输来介导不依赖逆转录酶的管状内体再循环
DOI：
10.1371/journal.pgen.1009607
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发表时间：
2021-06
期刊：
影响因子：
4.5
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Tian Y;Kang Q;Shi X;Wang Y;Zhang N;Ye H;Xu Q;Xu T;Zhang R
早期内体是内吞途径上的分选中心，其中分选连接蛋白（SNX）对形成具有不同分选功能的不同膜微区起重要作用。管状内体介导网格蛋白非依赖性内吞（CIE）货物向质膜的再循环。然而，小管形成的分子机制仍然知之甚少。在这里，我们筛选了秀丽隐杆线虫（C. habditis elegans）中所有SNX成员对ARF-6相关CIE再循环内体小管的影响。elegans）。我们确定SNX-3是产生再循环小管的重要因素。SNX-3的缺失破坏了C.优雅的。因此，再循环CIE蛋白hTAC的表面和总蛋白水平强烈降低。出乎意料的是，逆转录组分VPS-26/-29/-35的耗尽没有类似的效果，这意味着逆转录三聚体在该过程中被降解。我们确定hTAC被ESCRT复合物捕获并转运到溶酶体中以在snx-3突变体中快速降解。有趣的是，EEA-1越来越多地在早期内体上募集，并定位于snx-3突变体肠道中含有hTAC的结构。我们还表明，SNX 3和EEA 1相互竞争结合到富含磷脂酰肌醇-3-磷酸的早期内体在Hela细胞。我们的数据首次表明，PX域只有C。elegans SNX-3组织管状内体用于有效再循环，并通过与EEA-1竞争结合早期内体而从成熟的分选内体中回收CIE货物。然而，我们的研究结果提出了问题，SNX-3如何在不存在逆转录三聚体复合物的情况下将货物捕获和膜重塑偶联。
Early endosomes are the sorting hub on the endocytic pathway, wherein sorting nexins (SNXs) play important roles for formation of the distinct membranous microdomains with different sorting functions. Tubular endosomes mediate the recycling of clathrin-independent endocytic (CIE) cargoes back toward the plasma membrane. However, the molecular mechanism underlying the tubule formation is still poorly understood. Here we screened the effect on the ARF-6-associated CIE recycling endosomal tubules for all the SNX members in Caenorhabditis elegans (C. elegans). We identified SNX-3 as an essential factor for generation of the recycling tubules. The loss of SNX-3 abolishes the interconnected tubules in the intestine of C. elegans. Consequently, the surface and total protein levels of the recycling CIE protein hTAC are strongly decreased. Unexpectedly, depletion of the retromer components VPS-26/-29/-35 has no similar effect, implying that the retromer trimer is dispensable in this process. We determined that hTAC is captured by the ESCRT complex and transported into the lysosome for rapid degradation in snx-3 mutants. Interestingly, EEA-1 is increasingly recruited on early endosomes and localized to the hTAC-containing structures in snx-3 mutant intestines. We also showed that SNX3 and EEA1 compete with each other for binding to phosphatidylinositol-3-phosphate enriching early endosomes in Hela cells. Our data demonstrate for the first time that PX domain-only C. elegans SNX-3 organizes the tubular endosomes for efficient recycling and retrieves the CIE cargo away from the maturing sorting endosomes by competing with EEA-1 for binding to the early endosomes. However, our results call into question how SNX-3 couples the cargo capture and membrane remodeling in the absence of the retromer trimer complex.
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