The host ubiquitin-dependent segregase VCP/p97 is required for the onset of human cytomegalovirus replication

PLoS Pathogens

Yao-Tang Lin¹  Finn Grey¹  James Prendergast¹ 

[1] Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom

关键词: Small interfering RNAs;    Viral replication;    Exon mapping;    Alternative splicing;    Transfection;    Gene expression;    Human cytomegalovirus;    Viral gene expression;   

DOI  :  10.1371/journal.ppat.1006329

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The human cytomegalovirus major immediate early proteins IE1 and IE2 are critical drivers of virus replication and are considered pivotal in determining the balance between productive and latent infection. IE1 and IE2 are derived from the same primary transcript by alternative splicing and regulation of their expression likely involves a complex interplay between cellular and viral factors. Here we show that knockdown of the host ubiquitin-dependent segregase VCP/p97, results in loss of IE2 expression, subsequent suppression of early and late gene expression and, ultimately, failure in virus replication. RNAseq analysis showed increased levels of IE1 splicing, with a corresponding decrease in IE2 splicing following VCP knockdown. Global analysis of viral transcription showed the expression of a subset of viral genes is not reduced despite the loss of IE2 expression, including UL112/113. Furthermore, Immunofluorescence studies demonstrated that VCP strongly colocalised with the viral replication compartments in the nucleus. Finally, we show that NMS-873, a small molecule inhibitor of VCP, is a potent HCMV antiviral with potential as a novel host targeting therapeutic for HCMV infection.

【 授权许可】

CC BY