Min-Hua Luo, Wei Wang, Qiyi Tang, Yongxuan Yao, Bo Yang, Xuan Jiang, Jin-Yan Sun, Xian-Zhang Wang, Zhen-Li Huang, Hong Yang, Fei Zhao, William J Britt, Simon Rayner, Michael A McVoy, Xi-Juan Liu, Yanyi Wang, Yun Miao
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 infectious virus yield. However, WDR5 knockdown dramatically reduced infectious viral 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 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 interesting regulatory mechanism and a potential antiviral target.IMPORTANCE Human cytomegalovirus (HCMV) has a large (∼235-kb) genome with over 170 ORFs 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 nuclear egress of viral capsids, resulting in 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 anti-viral therapy.