Activation of host translational control pathways by a viral developmental switch.
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.
Arias
Carolina
C
Department of Microbiology and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
Walsh
Derek
D
Harbell
Jack
J
Wilson
Angus C
AC
Mohr
Ian
I
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000821:virology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C411571:EIF4ENIF1 protein, human; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D029543:Nucleocytoplasmic Transport Proteins; D010750:Phosphoproteins; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases