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J. Biol. Chem., Vol. 278, Issue 19, 16630-16641, May 9, 2003
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From the Transcription factors of the interferon
regulatory factor (IRF) family have been identified as critical
mediators of early inflammatory gene transcription in infected cells.
We have shown previously that IRF-5, like IRF-3 and IRF-7, is a
direct transducer of virus-mediated signaling and plays a role in the
expression of multiple cytokines/chemokines. The present study is
focused on the molecular mechanisms underlying the formation and
function of IRF-5/IRF-7 heterodimers in infected cells. The interaction between IRF-5 and IRF-7 is not cooperative and results in a repression rather than enhancement of IFNA gene transcription. The
formation of the IRF-5/IRF-7 heterodimer is dependent on IRF-7
phosphorylation, as shown by the glutathione S-transferase
pull-down and immunoprecipitation assays. Mapping of the interaction
domain revealed that formation of IRF-5/IRF-7 heterodimers occurs
through the amino terminus resulting in a masking of the DNA binding
domain, the consequent alteration of the composition of the
enhanceosome complex binding to IFNA promoters in
vivo, and modulation of the expression profile of
IFNA subtypes. Thus, these results indicate that
IRF-5 can act as both an activator and a repressor of
IFN gene induction dependent on the IRF-interacting
partner, and IRF-5 may be a part of the regulatory network
that ensures timely expression of the immediate early inflammatory genes.
Virus-induced Heterodimer Formation between
IRF-5 and IRF-7 Modulates Assembly of the
IFNA Enhanceosome in Vivo and Transcriptional
Activity of IFNA Genes*
§,, and¶
Sidney Kimmel Comprehensive Cancer Center
and ¶ Department of Molecular Biology and Genetics, and The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21231
*
This work was supported by National Institutes of
Health Grants R21AI19737-19 and R01AI/CA19737-19A1 (to P. M. P.) and
an Anticancer Drug Development Pharmacology-Oncology Training Grant (to
B. J. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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