A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus.
A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus.
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DOI：
10.1371/journal.ppat.1006253
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发表时间：
2017-03
期刊：
影响因子：
6.7
通讯作者：
Qu F
中科院分区：
文献类型：
--
作者：
Zhang XF;Sun R;Guo Q;Zhang S;Meulia T;Halfmann R;Li D;Qu F
不同的动植物病毒通过重复感染排斥（SIE）阻断相同或高度相似的病毒对宿主细胞的再感染，这是一种广泛观察到但知之甚少的现象。在这里，我们证明，芜菁皱缩病毒（TCV）的SIE是完全由p28，由这种病毒编码的两个复制蛋白之一。从TCV复制子表达的p28对不同的TCV复制子产生强SIE。瞬时表达的p28，与TCV复制子同时或提前递送，在很大程度上再现了这种抑制活性。有趣的是，p28介导的SIE被C-末端融合的表位标签或荧光蛋白显著增强，但被N-末端修饰减弱，并且它与p28补充p28缺陷TCV复制子的复制的能力负相关。引人注目的是，SIE阳性细胞中的p28形成大的、移动的点状内含物，其反式聚集非聚结的、SIE缺陷的、但具有复制能力的p28突变体。这些结果支持一个模型，假定TCV SIE是由多聚体p28复合物的形成，能够拦截从超感染基因组翻译的新鲜p28单体，从而消除超感染复制。该模型可以被证明适用于其他RNA病毒，并为抗病毒治疗提供新的靶点。超感染排斥（SIE）被许多病毒用来保护它们的宿主细胞免受相同或高度相似病毒的二次入侵。我们描述了一个革命性的发现，自我永存的聚结的病毒编码的复制蛋白作为一种新的机制SIE。我们的研究结果进一步表明，SIE的主要目标很可能是子代病毒基因组，而不是超级感染者，其目标是阻止子代病毒在“亲本”病毒所在的细胞中重新增殖，从而最大限度地减少复制错误的增殖。因此，本研究揭示的一般机制框架可能在具有不同基因组结构的病毒和宿主生物中高度保守，并可能成为抗病毒治疗的有效靶点。
Diverse animal and plant viruses block the re-infection of host cells by the same or highly similar viruses through superinfection exclusion (SIE), a widely observed, yet poorly understood phenomenon. Here we demonstrate that SIE of turnip crinkle virus (TCV) is exclusively determined by p28, one of the two replication proteins encoded by this virus. p28 expressed from a TCV replicon exerts strong SIE to a different TCV replicon. Transiently expressed p28, delivered simultaneously with, or ahead of, a TCV replicon, largely recapitulates this repressive activity. Interestingly, p28-mediated SIE is dramatically enhanced by C-terminally fused epitope tags or fluorescent proteins, but weakened by N-terminal modifications, and it inversely correlates with the ability of p28 to complement the replication of a p28-defective TCV replicon. Strikingly, p28 in SIE-positive cells forms large, mobile punctate inclusions that trans-aggregate a non-coalescing, SIE-defective, yet replication-competent p28 mutant. These results support a model postulating that TCV SIE is caused by the formation of multimeric p28 complexes capable of intercepting fresh p28 monomers translated from superinfector genomes, thereby abolishing superinfector replication. This model could prove to be applicable to other RNA viruses, and offer novel targets for antiviral therapy. Superinfection exclusion (SIE) is employed by many viruses to guard their host cells against secondary invasions by the same or highly similar viruses. We describe a transformative discovery that self-perpetuating coalescence of a virus-encoded replication protein serves as a novel mechanism for SIE. Our findings further suggest that the primary targets of SIE may very well be progeny viral genomes rather than superinfectors, with the goal of blocking renewed multiplication of progeny viruses in the cells resided by “parental” viruses, thereby minimizing the proliferation of replication errors. Consequently, the general mechanistic framework revealed in this study may be highly conserved among viruses with diverse genome structures and host organisms, and could become a potent target for antiviral therapy.