Human host factors required for influenza virus replication.
Human host factors required for influenza virus replication.
复制标题
作者：
甲型流感病毒是一种RNA病毒，编码多达11种蛋白质，这种小的编码能力要求病毒在其生命周期的许多方面使用宿主细胞机制。了解这些宿主细胞的需求不仅可以让我们了解病毒利用的分子途径，还可以为抗病毒药物开发提供进一步的靶点。在这里，我们使用一个综合系统的方法，基于全基因组RNA干扰筛选，以确定早期流感病毒复制所需的295个细胞辅因子。在这一组中，那些参与激酶调节的信号传导，泛素化和磷酸酶活性是最高度富集的，181个因子组装成一个非常重要的宿主-病原体相互作用网络。此外，295个因子中的219个被证实是野生型流感病毒有效生长所必需的，并且对基因子集的进一步分析显示了病毒进入所必需的23个因子，包括空泡ATP酶（vATP酶）和COPI蛋白家族的成员、成纤维细胞生长因子受体（FGFR）蛋白和糖原合成酶激酶3（GSK 3）-β。此外，10个蛋白质被证实参与流感病毒复制的后进入步骤。这些包括核输入组分、蛋白酶和钙/钙调蛋白依赖性蛋白激酶（CaM激酶）IIβ（CAMK 2B）。值得注意的是，猪源H1N1流感病毒的生长也依赖于所确定的宿主因子，并且我们表明包括vATPase和CAMK 2B在内的几种因子的小分子抑制剂拮抗流感病毒复制。
Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host–pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-β. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIβ (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
登录
查看更多内容
影响因子：
64.8
作者：
Sessions, October M.;Barrows, Nicholas J.;Souza-Neto, Jayme A.;Robinson, Timothy J.;Hershey, Christine L.;Rodgers, Mary A.;Ramirez, Jose L.;Dimopoulos, George;Yang, Priscilla L.;Pearson, James L.;Garcia-Blanco, Mariano A.
通讯作者：
Garcia-Blanco, Mariano A.
影响因子：
30.3
作者：
Zhou, Honglin;Xu, Min;Espeseth, Amy S.
通讯作者：
Espeseth, Amy S.
影响因子：
64.8
作者：
Krishnan, Manoj N.;Ng, Aylwin;Sukumaran, Bindu;Gilfoy, Felicia D.;Uchil, Pradeep D.;Sultana, Hameeda;Brass, Abraham L.;Adametz, Rachel;Tsui, Melody;Qian, Feng;Montgomery, Ruth R.;Lev, Sima;Mason, Peter W.;Koski, Raymond A.;Elledge, Stephen J.;Xavier, Ramnik J.;Agaisse, Herve;Fikrig, Erol
通讯作者：
Fikrig, Erol
DOI：
10.1038/nrd2175
发表时间：
2006-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
De Clercq E
通讯作者：
De Clercq E
影响因子：
64.5
作者：
Kutay, U;Bischoff, FR;Gorlich, D
通讯作者：
Gorlich, D