Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform
Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform
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DOI：
10.1073/pnas.1302564110
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发表时间：
2013-07-02
影响因子：
11.1
通讯作者：
Hang, Howard C.
中科院分区：
文献类型：
--
作者：
Charron, Guillaume;Li, Melody M. H.;Hang, Howard C.
S-异戊二烯化是一种重要的脂质修饰，可将蛋白质靶向膜，以实现真核生物中的细胞信号传导和囊泡运输。由于 S-异戊二烯化蛋白通常是肿瘤发生、先天性疾病和微生物发病机制的关键效应物，因此仍然需要强大的蛋白质组学方法来对特定细胞类型和疾病状态下的这些脂化蛋白进行生化表征。在这里，我们报告说，使用改进的炔-类异戊二烯化学报告基因对巨噬细胞进行生物正交蛋白质组学，能够大规模分析异戊二烯化蛋白质，并发现未注释的脂质化蛋白质，例如锌指抗病毒蛋白（ZAP）的异构体特异性S-法呢基化。值得注意的是，S-法呢基化对于将 ZAP (ZAPL/PARP-13.1/zc3hav1) 长亚型靶向内溶酶体并增强该免疫效应子的抗病毒活性至关重要。这些研究证明了类异戊二烯化学报告基因在异戊二烯化蛋白质的蛋白质组学分析中的实用性，并揭示了蛋白质异戊二烯化在宿主防御病毒感染中的作用。
S-prenylation is an important lipid modification that targets proteins to membranes for cell signaling and vesicle trafficking in eukaryotes. As S-prenylated proteins are often key effectors for oncogenesis, congenital disorders, and microbial pathogenesis, robust proteomic methods are still needed to biochemically characterize these lipidated proteins in specific cell types and disease states. Here, we report that bioorthogonal proteomics of macrophages with an improved alkyne-isoprenoid chemical reporter enables large-scale profiling of prenylated proteins, as well as the discovery of unannotated lipidated proteins such as isoform-specific S-farnesylation of zinc-finger antiviral protein (ZAP). Notably, S-farnesylation was crucial for targeting the long-isoform of ZAP (ZAPL/PARP-13.1/zc3hav1) to endolysosomes and enhancing the antiviral activity of this immune effector. These studies demonstrate the utility of isoprenoid chemical reporters for proteomic analysis of prenylated proteins and reveal a role for protein prenylation in host defense against viral infections.