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PMID: 10438822 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300.

Journal of virology ·Vol. 73 ·No. 9 ·1999-09-00 ·Pages 7334-42

Burýsek L, Yeow WS, Lubyová B, Kellum M, Schafer SL, Huang YQ, Pitha PM

Abstract

Human herpesvirus 8/Kaposi sarcoma-associated virus (HHV-8/KSHV) contains, in addition to genes required for viral replication, a unique set of nonstructural genes which may be part of viral mimicry and contribute to viral replication and pathogenesis in vivo. Among these, HHV-8 encodes four open reading frames (ORFs) that showed homology to the transcription factors of the interferon regulatory factor (IRF) family. The ORF K9, viral IRF 1 (vIRF-1), has been cloned, and it was shown that, when overexpressed, it down modulates the interferon-mediated transcriptional activation of the interferon-stimulated gene 15 (ISG 15) promoter, and the role of vIRF-1 in viral mimicry was implied. However, the molecular mechanism of this effect has not been clarified. Here, we extend this observation and show that vIRF-1 also downregulates the transcriptional activity of IFNA gene promoter in infected cells by interfering with the transactivating activity of cellular IRFs, including IRF-1 and IRF-3. We further show that ectopic expression of vIRF-1 in NIH 3T3 cells confers resistance to tumor necrosis factor alpha-induced apoptosis. While vIRF-1 is unable to bind DNA with the same specificity as cellular IRFs, we demonstrate by in vitro binding assay that it can associate with the family of cellular IRFs, such as IRF-1 and the interferon consensus sequence binding protein. vIRF-1 interaction domain was localized between amino acids (aa) 152 and 243. While no binding between the full-size IRF-3 and vIRF-1 could be detected by the same assay, we show that vIRF-1 also targets the carboxy-terminal region (aa 1623 to 2414) of the transcriptional coactivator p300 which could also bind IRF-3 and IRF-1. These results demonstrate that vIRF-1 can modulate the transcription of the IFNA genes by direct heterodimerization with members of the IRF family, as well as by competitive binding with cellular transcription factors to the carboxy-terminal region of p300.

MeSH Terms
3T3 Cells Animals Apoptosis Binding Sites DNA-Binding Proteins/metabolism,physiology E1A-Associated p300 Protein Herpesvirus 8, Human/metabolism Humans Interferon Regulatory Factor-1 Interferon Regulatory Factor-2 Interferon Regulatory Factor-3 Interferon-alpha/genetics Mice Nuclear Proteins/metabolism Phosphoproteins/metabolism,physiology Promoter Regions, Genetic Repressor Proteins Trans-Activators/metabolism Transcription Factors/metabolism
Chemicals
DNA-Binding Proteins IRF1 protein, human IRF2 protein, human IRF3 protein, human Interferon Regulatory Factor-1 Interferon Regulatory Factor-2 Interferon Regulatory Factor-3 Interferon-alpha Irf1 protein, mouse Irf2 protein, mouse Irf3 protein, mouse Nuclear Proteins Phosphoproteins Repressor Proteins Trans-Activators Transcription Factors E1A-Associated p300 Protein Ep300 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Burýsek L
Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Yeow W S
Lubyová B
Kellum M
Schafer S L
Huang Y Q
Pitha P M
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.73.9.7334-7342.1999
Published
1999-09-00
Pages
7334-42
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC104259
Subset
IM
Grants
NIAID NIH HHS · R01 AI019737 · United States
NIAID NIH HHS · R21 AI019737 · United States
NIAID NIH HHS · AI19737 · United States
NCI NIH HHS · CA76946 · United States
External Links
PubMed source DOI: 10.1128/JVI.73.9.7334-7342.1999 PMC Full Text View journal details
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