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Molecular and Cellular Biology, July 2000, p. 4814-4825, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Assembly of a Functional Beta Interferon Enhanceosome Is Dependent on ATF-2-c-jun Heterodimer Orientation

James V. Falvo,1 Bhavin S. Parekh,1,dagger Charles H. Lin,1,2 Ernest Fraenkel,1 and Tom Maniatis1,*

Department of Molecular and Cellular Biology1 and Department of Chemistry and Chemical Biology,2 Harvard University, Cambridge, Massachusetts 02138

Received 10 November 1999/Returned for modification 16 December 1999/Accepted 29 March 2000

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.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Ave., Cambridge, MA 02138. Phone: (617) 495-1811. Fax: (617) 495-3537. E-mail: maniatis{at}biohp.harvard.edu.

dagger Present address: GeneSoft Inc., South San Francisco, CA 94080.

Molecular and Cellular Biology, July 2000, p. 4814-4825, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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