Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA.
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Nat Immunol. 2019 Dec;20(12):1610-1620. doi: 10.1038/s41590-019-0527-6. Epub 2019 Nov 18.
The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host's ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.
病毒感染的初始反应是预期性的，宿主抗病毒限制因子和病原体传感器不断地检测细胞，通过干扰素的合成和下游活性迅速地产生抗病毒反应。在病原体清除后，宿主能够解决这种抗病毒反应并恢复到体内平衡的能力至关重要。在这里，我们发现 RNA 结合蛋白 ZAP 的同工型既作为直接的抗病毒限制因子，也作为干扰素反应的调节因子。ZAP 的短同工型与几种宿主干扰素信使 RNA 结合并介导其降解，因此作为干扰素反应的负反馈调节剂。相比之下，ZAP 的长同工型具有抗病毒功能，并不调节干扰素。两种同工型含有相同的 RNA 靶向结构域，但细胞内定位的差异调节了它们对宿主 RNA 与病毒 RNA 的特异性，这导致在固有免疫反应过程中对病毒复制产生不同的影响。
