Packaging of influenza virus genome: robustness of selection.
Packaging of influenza virus genome: robustness of selection.
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流感病毒基因组的包装：选择的稳健性。
DOI：
10.1073/pnas.1206736109
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Noda T
中科院分区：
文献类型：
--
作者：
高山正彦;作道章一;Noda T
流感病毒的独特之处在于它的基因组就像人类染色体一样是碎片化的。这种基因组分割赋予了进化优势，如基因重组，这有助于大流行毒株的出现(1)。和人类一样，流感病毒必须将其基因组准确地传递给后代，才能保证物种的生存。这个过程很复杂，但在生物学上很有趣，因为病毒基因组必须从病毒感染细胞中的大量宿主遗传物质中选择出来，而且每个传染性病毒颗粒必须包含所有的基因组片段。然而，尽管进行了详尽的研究，流感病毒颗粒确保正确包装其片段基因组的机制在很大程度上仍不清楚。在PNAS上，Chou等人(2)开发了一个实验系统来解决这个长期的谜题，这样做对我们对流感病毒基因组包装过程的理解做出了重要贡献。流感病毒基因组由8个单链负义RNA片段组成。历史上，人们提出了两种模型来解释病毒RNA片段被包装成后代病毒颗粒的机制：随机包装模型和选择性包装模型(3)。前一种模型假设各种病毒RNA片段被任意整合到病毒颗粒中，只有当每个病毒RNA片段至少有一个拷贝被随机整合到颗粒中时，才会产生感染性颗粒（图1A）。传染性法氏囊病病毒具有双片段dsRNA基因组，采用该系统(4)。后一种模型提出，每个病毒RNA片段都有一个独特的包装信号序列，将其与其他病毒RNA片段区分开来，从而确保将8个独特的病毒RNA片段包装到每个病毒颗粒中（图1A）。囊病毒科的dsRNA噬菌体是使用该模型的生物体的好例子(5)。然而，就流感病毒而言，关于其基因组包装机制的确凿证据仍然缺乏，争议仍然存在。支持流感病毒选择性包装模型的早期证据来自对缺陷干扰（DI）病毒rna的分析（6,7）。DI片段是由于编码区内部缺失而产生的病毒RNA片段，它竞争性地抑制其亲本病毒RNA片段的包装，但不抑制其他病毒RNA片段的包装，并优先结合到子代病毒颗粒中。这种片段特异性竞争意味着每个病毒RNA片段在基因组包装过程中是不同的，并且每个DI片段都具有所谓的基因组包装信号。后来，反向遗传学研究提供了令人信服的证据，证明所有8个病毒RNA片段都具有片段特异性的包装信号序列，可以有效地整合到子代病毒颗粒中（3,8），正如选择性包装模型所预测的那样。这些包装信号包括病毒RNA片段两端的二部序列，其中不仅包含所有8个病毒RNA片段共有的保守启动子区域，还包含与启动子区域相邻的蛋白质编码区和片段特异性非编码区。因此，每个病毒RNA片段的信号序列都是独特的，这在选择8个不同的病毒RNA片段时可能是重要的。EM分析也强烈支持选择性包装模型(9)。八种核糖核蛋白复合物（RNPs），由病毒RNA片段、核蛋白和…
Influenza virus is unique in that its genome is fragmented just like human chromosomes. This genome segmentation confers evolutionary advantages such as genetic reassortment, which contributes to the emergence of pandemic strains (1). Also like humans, the influenza virus must pass its genome accurately onto its offspring for species survival. This process is complicated but biologically interesting because the viral genome must be selected from a large pool of host genetic materials in the virus-infected cell and each infectious virus particle must contain all of the genome fragments. However, despite exhaustive research, the mechanisms by which the influenza virus particle ensures correct packaging of its fragmented genome have remained largely unclear. In PNAS, Chou et al.(2) develop an experimental system to address this long-time enigma and, in so doing, make important contributions to our understanding of the genome packaging process of the influenza virus. The influenza virus genome is composed of eight single-stranded, negative-sense RNA segments. Historically, two models have been proposed to explain the mechanisms by which the viral RNA segments are packaged into progeny virus particles: the random packaging model and the selective packaging model (3). The former model assumes that the various viral RNA segments are arbitrarily incorporated into virus particles, and infectious particles are produced only when at least one copy of each viral RNA segment is incorporated into the particle by chance (Fig. 1A). Infectious bursal disease virus, which possesses a two-segmented dsRNA genome, employs this system (4). The latter model proposes that each viral RNA segment has a distinct packaging signal sequence that differentiates it from the other viral RNA segments, ensuring the packaging of eight unique viral RNA segments into each virus particle (Fig. 1A). The dsRNA bacteriophages of the Cystoviridae family are good examples of organisms that use this model (5). With respect to the influenza virus, however, conclusive evidence regarding its genome packaging mechanism is still lacking, and controversy remains. Early evidence in support of the selective packaging model for influenza virus came from analyses of defective-interfering (DI) viral RNAs (6, 7). The DI segment, which is derived from a viral RNA segment as a result of an internal deletion in the coding region, competitively inhibits the packaging of its parental viral RNA segment but not that of other viral RNA segments, and is preferentially incorporated into progeny virus particles. Such segment-specific competition implies that each viral RNA segment is distinct during the genome packaging process and that each DI segment possesses a so-called genome packaging signal. Later, reverse genetics studies provided compelling evidence that all eight viral RNA segments possess segment-specific packaging signal sequences for their efficient incorporation into progeny virus particles (3, 8), as predicted in the selective packaging model. These packaging signals include bipartite sequences at both ends of the viral RNA segment, which house not only the conserved promoter region that is common to all eight viral RNA segments, but also protein-coding and segment-specific noncoding regions adjacent to the promoter region. Thus, the signal sequences are unique to each viral RNA segment, which may be important during the selection of the eight different viral RNA segments. EM analyses also strongly support the selective packaging model (9). Eight ribonucleoprotein complexes (RNPs), which are composed of the viral RNA segments, nucleoproteins, and …