School of Biochemistry, Faculty of Life Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2201980119. doi: 10.1073/pnas.2201980119. Epub 2022 Jun 13.
Endosomal sorting maintains cellular homeostasis by recycling transmembrane proteins and associated proteins and lipids (termed "cargoes") from the endosomal network to multiple subcellular destinations, including retrograde traffic to the -Golgi network (TGN). Viral and bacterial pathogens subvert retrograde trafficking machinery to facilitate infectivity. Here, we develop a proteomic screen to identify retrograde cargo proteins of the endosomal SNX-BAR sorting complex promoting exit 1 (ESCPE-1). Using this methodology, we identify Neuropilin-1 (NRP1), a recently characterized host factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as a cargo directly bound and trafficked by ESCPE-1. ESCPE-1 mediates retrograde trafficking of engineered nanoparticles functionalized with the NRP1-interacting peptide of the SARS-CoV-2 spike (S) protein. CRISPR-Cas9 deletion of ESCPE-1 subunits reduces SARS-CoV-2 infection levels in cell culture. ESCPE-1 sorting of NRP1 may therefore play a role in the intracellular membrane trafficking of NRP1-interacting viruses such as SARS-CoV-2.
内体分选通过从内体网络中将跨膜蛋白和相关蛋白及脂质（称为“货物”）循环再利用到多个亚细胞目的地，从而维持细胞内稳态，包括逆行运输到 -高尔基体网络（TGN）。病毒和细菌病原体颠覆逆行运输机制以促进感染性。在这里，我们开发了一种蛋白质组学筛选方法来鉴定内体 SNX-BAR 分选复合物促进出口 1（ESCPE-1）的逆行货物蛋白。使用这种方法，我们确定了神经纤毛蛋白 1（NRP1），它是严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的最近被表征的宿主因子，作为 ESCPE-1 直接结合和运输的货物。ESCPE-1 介导了工程化纳米颗粒的逆行运输，这些纳米颗粒被 SARS-CoV-2 刺突（S）蛋白的 NRP1 相互作用肽功能化。CRISPR-Cas9 敲除 ESCPE-1 亚基会降低细胞培养中 SARS-CoV-2 的感染水平。因此，ESCPE-1 分选 NRP1 可能在 NRP1 相互作用的病毒（如 SARS-CoV-2）的细胞内膜运输中发挥作用。
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