Activation of Host Translational Control Pathways by a Viral Developmental Switch

PLoS Pathogens

Carolina Arias¹  Derek Walsh¹  Ian Mohr¹  Angus C. Wilson¹  Jack Harbell² 

[1] Department of Microbiology and NYU Cancer Institute, New York University School of Medicine, New York, New York, United States of America;National Institute For Cellular Biotechnology, Dublin City University, Dublin, Ireland

关键词: Viral replication;    Messenger RNA;    Phosphorylation;    Protein translation;    Protein synthesis;    Immunoblotting;    Virus effects on host gene expression;    Kaposi's sarcoma-associated herpesvirus;   

DOI  :  10.1371/journal.ppat.1000334

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate.

【 授权许可】

CC BY