The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry
The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry
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DOI：
10.1038/s41564-018-0273-9
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发表时间：
2018-12-01
影响因子：
28.3
通讯作者：
Malim, Michael H.
中科院分区：
文献类型：
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作者：
Doyle, Tomas;Moncorge, Olivier;Malim, Michael H.
干扰素 (IFN) 通过上调 IFN 刺激的基因（其产物与病毒成分相互作用或改变细胞生理学以抑制病毒复制）来介导针对病毒病原体的细胞防御 (1-3)。可以抑制甲型流感病毒 (IAV)(4) 的 IFN 刺激基因包括粘病毒抗性 1 GTPase(5) 和 IFN 诱导的跨膜蛋白 3（参考文献（6,7））。在这里，我们使用异位表达和基因敲除来证明 IFN 诱导的 219 个氨基酸的人核受体共激活剂 7 (NCOA7) 短亚型是 IAV 以及通过内吞作用进入细胞的其他病毒（包括丙型肝炎病毒）的抑制剂。 NCOA7 与液泡 H+-ATP 酶 (V-ATP 酶) 相互作用，其表达促进细胞质囊泡酸化、溶酶体蛋白酶活性和内吞抗原的降解。 IAV 进入途径的逐步剖析表明 NCOA7 抑制病毒和内体膜的融合以及随后的病毒核糖核蛋白的核转位。因此，NCOA7提供了一种内溶酶体生理学的免疫调节机制，不仅抑制病毒从该区室进入胞质溶胶，而且还可以调节其他V-ATP酶相关的细胞过程，例如营养状态的生理调节，或抗原呈递细胞的成熟和功能。
Interferons (IFNs) mediate cellular defence against viral pathogens by upregulation of IFN-stimulated genes whose products interact with viral components or alter cellular physiology to suppress viral replication(1-3). Among the IFN-stimulated genes that can inhibit influenza A virus (IAV)(4) are the myxovirus resistance 1 GTPase(5) and IFN-induced transmembrane protein 3 (refs(6,7)). Here, we use ectopic expression and gene knockout to demonstrate that the IFN-inducible 219-amino acid short isoform of human nuclear receptor coactivator 7 (NCOA7) is an inhibitor of IAV as well as other viruses that enter the cell by endocytosis, including hepatitis C virus. NCOA7 interacts with the vacuolar H+-ATPase (V-ATPase) and its expression promotes cytoplasmic vesicle acidification, lysosomal protease activity and the degradation of endocy-tosed antigen. Step-wise dissection of the IAV entry pathway demonstrates that NCOA7 inhibits fusion of the viral and endosomal membranes and subsequent nuclear translocation of viral ribonucleoproteins. Therefore, NCOA7 provides a mechanism for immune regulation of endolysosomal physiology that not only suppresses viral entry into the cytosol from this compartment but may also regulate other V-ATPase-associated cellular processes, such as physiological adjustments to nutritional status, or the maturation and function of antigen-presenting cells.