Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis.
Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis.
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DOI：
10.1128/mbio.02325-17
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发表时间：
2018-05-22
期刊：
影响因子：
6.4
通讯作者：
Enjuanes L
中科院分区：
文献类型：
--
作者：
Castaño-Rodriguez C;Honrubia JM;Gutiérrez-Álvarez J;DeDiego ML;Nieto-Torres JL;Jimenez-Guardeño JM;Regla-Nava JA;Fernandez-Delgado R;Verdia-Báguena C;Queralt-Martín M;Kochan G;Perlman S;Aguilella VM;Sola I;Enjuanes L
病毒孔蛋白是一种具有离子通道活性的病毒蛋白，在病毒复制和致病等过程中发挥重要作用。许多冠状病毒(CoV)编码两种病毒孔蛋白，而严重急性呼吸综合征冠状病毒(SARS-CoV)编码三种蛋白：蛋白3a、E和8a。此外，蛋白质3a和E有一个PDZ结合基序(PBM)，它可以潜在地结合400多个含有PDZ结构域的细胞蛋白，使它们对细胞功能的控制具有潜在的重要意义。在本工作中，对SARS-CoV病毒孔蛋白的功能基序进行了比较研究，主要集中在E蛋白和3a蛋白的IC和PBM的作用上。我们的结果表明，全长的E和3a蛋白是SARS-CoV最大复制和毒力所必需的，而8a病毒对这些活性只有很小的影响。同时缺失E蛋白和3a蛋白的病毒是不能存活的，而其中任何一种蛋白的存在与功能的PBM一起恢复了病毒的活性。E蛋白IC活性及其PBM的存在是小鼠毒力所必需的。相反，蛋白3a中同源基序的存在或不存在并不影响病毒的致病性。因此，在小鼠的致病过程中，蛋白E的IC和PBM比蛋白3a的IC和PBM占优势。总之，这些结果显示了离子通道和PBM结构域在最佳病毒复制和致病机制中的关键作用，并表明病毒病毒素和PBM是抗病毒治疗和SARS-CoV减毒疫苗突变的合适靶点。
Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice. Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines.
影响因子：
2.2
作者：
Hsu HJ;Fischer WB
通讯作者：
Fischer WB