WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress.
WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress.
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WDR5 通过促进衣壳核排出来促进人类巨细胞病毒复制。
DOI：
10.1128/jvi.00207-18
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发表时间：
2018
影响因子：
5.4
通讯作者：
Zhao Fei
中科院分区：
文献类型：
--
作者：
Yang Bo;Liu Xi-Juan;Yao Yongxuan;Jiang Xuan;Wang Xian-Zhang;Yang Hong;Sun Jin-Yan;Miao Yun;Wang Wei;Huang Zhen-Li;Wang Yanyi;Tang Qiyi;Rayner Simon;Britt William J;McVoy Michael A;Luo Min-Hua;Zhao Fei
WD重复蛋白5(WDR5)是组装VISA相关复合体以诱导针对仙台病毒感染的I型干扰素抗病毒反应所必需的。然而，WDR5在DNA病毒感染中的作用还没有得到很好的描述。在此，我们报道了人类巨细胞病毒利用WDR5促进衣壳核外泄。WDR5在成纤维细胞中的过表达略微增加了感染性病毒的产量。然而，WDR5基因敲除显著降低了传染性病毒的滴度，仅略微降低了病毒基因组复制或基因表达。对病毒复制后期步骤的进一步研究发现，WDR5基因敲除显着削弱了病毒核出口复合体的形成，并导致更少的内核膜折叠。此外，与这些褶皱相关的衣壳较少，细胞质中的衣壳较少。WDR5的恢复部分逆转了这些效应。这些结果表明，WDR5基因敲除会损害衣壳蛋白的核出口，进而降低病毒滴度。这些发现揭示了宿主因子(S)的功能被病毒病原体篡夺以促进有效复制的重要作用。因此，WDR5代表了一个有趣的调控机制和潜在的抗病毒靶点。人类巨细胞病毒(∼)有一个大的基因组(WDR35kb)，有170多个开放阅读框，并利用大量的细胞因子来促进其复制。在感染过程中，HCMV感染增加了WD重复序列蛋白5(WDR5)的蛋白水平，WDR5的过表达增强了病毒的复制，而WDR5的敲除显著地抑制了病毒的复制。我们的结果表明，WDR5促进了病毒衣壳的核外泄，耗尽了WDR5，导致感染性病毒粒子的产生显著减少。这是WDR5支持DNA病毒HCMV复制的第一份报告，并强调了抗病毒治疗的新靶点。
WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA-associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target.IMPORTANCEHuman cytomegalovirus (HCMV) has a large (∼235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy.