McNally Kerrie E, Faulkner Rebecca, Steinberg Florian, Gallon Matthew, Ghai Rajesh, Pim David, Langton Paul, Pearson Neil, Danson Chris M, Nägele Heike, Morris Lindsey L, Singla Amika, Overlee Brittany L, Heesom Kate J, Sessions Richard, Banks Lawrence, Collins Brett M, Berger Imre, Billadeau Daniel D, Burstein Ezra, Cullen Peter J
School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
Department of Internal Medicine and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nat Cell Biol. 2017 Oct;19(10):1214-1225. doi: 10.1038/ncb3610. Epub 2017 Sep 11.
Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of αβ integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.
在被内吞进入内体网络后，整合膜蛋白会进行分选以便进行溶酶体降解，或者被回收并循环回到细胞表面。在这里，我们描述了一种古老且保守的多蛋白复合物的发现，该复合物协调货物回收和循环，并且重要的是，在生化和功能上与已确立的逆转录酶途径不同。我们将这个复合物称为“retriever”；它是一个由DSCR3、C16orf62和VPS29组成的异源三聚体，与逆转录酶有显著相似性。我们确定retriever与货物衔接蛋白分选连接蛋白17（SNX17）结合，并与CCC（CCDC93、CCDC22、COMMD）和WASH复合物耦合，以防止溶酶体降解并促进αβ整合素的细胞表面循环。通过定量蛋白质组学分析，我们鉴定出超过120种细胞表面蛋白，包括许多整合素、信号受体和溶质转运体，它们需要SNX17-retriever来维持其表面水平。我们对retriever的鉴定建立了一条主要的内体回收和循环途径。
