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Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J Virol 2010 Aug;84(15):7803-14

Date

05/28/2010

Pubmed ID

20504932

Pubmed Central ID

PMC2897612

DOI

10.1128/JVI.00139-10

Scopus ID

2-s2.0-77954485440   129 Citations

Abstract

The human cytomegalovirus (HCMV) virion protein pUL83 (also termed pp65) inhibits the expression of interferon-inducible cellular genes. In this work we demonstrate that pUL83 is also important for efficient induction of transcription from the viral major immediate-early promoter. Infection with a mutant virus containing a premature translation termination codon in the UL83 open reading frame (ORF) (UL83Stop) resulted in decreased transcription from the major immediate-early promoter in a time- and multiplicity-dependent manner. Expression of pUL83 alone is capable of transactivating the promoter in a reporter assay, and pUL83 associates with the promoter in infected cells. To investigate the mechanism by which the protein regulates the major immediate-early promoter, we utilized a mutant virus expressing an epitope-tagged pUL83 from its own promoter to identify protein binding partners for pUL83 during infection. We identified and confirmed the interaction of pUL83 with cellular IFI16 family members throughout the course of HCMV infection. pUL83 recruits IFI16 to the major immediate-early promoter, and IFI16 binding at the promoter is dependent upon the presence of pUL83. Consistent with the results obtained with the UL83Stop virus, infection of IFI16 knockdown cells with wild-type virus resulted in decreased levels of immediate-early transcripts compared to those of control cells. These data identify a previously unknown role for pUL83 in the initiation of the human cytomegalovirus gene expression cascade.

Author List

Cristea IM, Moorman NJ, Terhune SS, Cuevas CD, O'Keefe ES, Rout MP, Chait BT, Shenk T

Author

Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cells, Cultured
Codon, Nonsense
Cytomegalovirus
DNA, Viral
Fibroblasts
Gene Knockdown Techniques
Genes, Immediate-Early
Genes, Reporter
Host-Pathogen Interactions
Humans
Mutation, Missense
Nuclear Proteins
Phosphoproteins
Promoter Regions, Genetic
Protein Binding
Protein Interaction Mapping
Transcriptional Activation
Viral Matrix Proteins