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PMID: 10848607 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Assembly of a functional beta interferon enhanceosome is dependent on ATF-2-c-jun heterodimer orientation.

Molecular and cellular biology ·Vol. 20 ·No. 13 ·2000-07-00 ·Pages 4814-25

Falvo JV, Parekh BS, Lin CH, Fraenkel E, Maniatis T

Abstract

Heterodimeric transcription factors, including the basic region-leucine zipper (bZIP) protein ATF-2-c-jun, are well-characterized components of an enhanceosome that mediates virus induction of the human beta interferon (IFN-beta) gene. Here we report that within the IFN-beta enhanceosome the ATF-2-c-jun heterodimer binds in a specific orientation, which is required for assembly of a complex between ATF-2-c-jun and interferon regulatory factor 3 (IRF-3). We demonstrate that correct orientation of the ATF-2-c-jun binding site is required for virus induction of the IFN-beta gene and for IRF-3-dependent activation of a composite ATF-2- c-jun-IRF site in the IFN-beta promoter. We also show that in vitro the DNA-bound ATF-2-c-jun heterodimer adopts a fixed orientation upon the binding of IRF-3 at an adjacent site in the IFN-beta enhancer and that the DNA-binding domain of IRF-3 is sufficient to mediate this effect. In addition, we show that the DNA-binding domain of ATF-2 is necessary and sufficient for selective protein-protein interactions with IRF-3. Strikingly, in vivo chromatin immunoprecipitation experiments with IFN-beta reporter constructs reveal that recruitment of IRF-3 to the IFN-beta promoter upon virus infection is dependent on the orientation of the ATF-2-c-jun heterodimer binding site. These observations demonstrate functional and physical cooperativity between the bZIP and IRF transcription factor families and illustrate the critical role of heterodimeric transcription factors in formation of the IFN-beta enhanceosome.

MeSH Terms
Activating Transcription Factor 2 Amino Acid Sequence Base Sequence Binding Sites Cross-Linking Reagents Cyclic AMP Response Element-Binding Protein/metabolism DNA/metabolism DNA-Binding Proteins/metabolism Dimerization Enhancer Elements, Genetic Glutathione Transferase/genetics,metabolism HeLa Cells/virology Humans Interferon Regulatory Factor-1 Interferon Regulatory Factor-2 Interferon Regulatory Factor-3 Interferon-beta/genetics,metabolism Leucine Zippers Molecular Sequence Data Mutagenesis, Site-Directed Phosphoproteins/metabolism Promoter Regions, Genetic Proto-Oncogene Proteins c-jun/metabolism Recombinant Proteins/genetics,metabolism Regulatory Sequences, Nucleic Acid Repressor Proteins Response Elements Transcription Factors/metabolism
Chemicals
ATF2 protein, human Activating Transcription Factor 2 Cross-Linking Reagents Cyclic AMP Response Element-Binding Protein DNA-Binding Proteins IRF1 protein, human IRF2 protein, human IRF3 protein, human Interferon Regulatory Factor-1 Interferon Regulatory Factor-2 Interferon Regulatory Factor-3 Phosphoproteins Proto-Oncogene Proteins c-jun Recombinant Proteins Repressor Proteins Transcription Factors Interferon-beta DNA Glutathione Transferase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Falvo J V
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Parekh B S
Lin C H
Fraenkel E
Maniatis T
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.13.4814-4825.2000
Published
2000-07-00
Pages
4814-25
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85927
Subset
IM
Grants
NIAID NIH HHS · R01 AI020642 · United States
NIAID NIH HHS · AI20642 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.13.4814-4825.2000 PMC Full Text View journal details
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