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Molecular and Cellular Biology, March 1999, p. 1810-1820, Vol. 19, No. 3
0270-7306/99

The Histone Acetylase PCAF Is a Phorbol-Ester-Inducible Coactivator of the IRF Family That Confers Enhanced Interferon Responsiveness

Atsuko Masumi,dagger I-Ming Wang, Bruno Lefebvre, Xing-Jiao Yang, Yoshihiro Nakatani, and Keiko Ozato*

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2753

Received 6 July 1998/Returned for modification 14 September 1998/Accepted 19 November 1998

Transcription factors of the interferon regulatory factor (IRF) family bind to the type I interferon (IFN)-responsive element (ISRE) and activate transcription from IFN-inducible genes. To identify cofactors that associate with IRF proteins, DNA affinity binding assays were performed with nuclear extracts prepared from tissue culture cells. The results demonstrated that the endogenous IRFs bound to the ISRE are complexed with the histone acetylases, PCAF, GCN5, and p300/CREB binding protein and that histone acetylase activities are accumulated on the IRF-ISRE complexes. By testing recombinant proteins, we show that PCAF directly binds to some but not all members of the IRF family through distinct domains of the two proteins. This interaction was functionally significant, since transfection of PCAF strongly enhanced IRF-1- and IRF-2-dependent promoter activities. Further studies showed that expression of PCAF and other histone acetylases was markedly induced in U937 cells upon phorbol ester treatment, which led to increased recruitment of PCAF to the IRF-ISRE complexes. Coinciding with the induction of histone acetylases, phorbol ester markedly enhanced IFN-alpha -stimulated gene expression in U937 cells. Supporting the role for PCAF in conferring IFN responsiveness, transfection of PCAF into U937 cells led to a large increase in IFN-alpha -inducible promoter activity. These results demonstrate that PCAF is a phorbol ester-inducible coactivator of the IRF proteins which contributes to the establishment of type I IFN responsiveness.


* Corresponding author. Mailing address: Laboratory of Molecular Growth Regulation, Bldg. 6, Rm. 2A01, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2735. Phone: (301) 496-9184. Fax: (301) 480-9354. E-mail: ozatok{at}nih.gov.

dagger Present address: National Institute of Infectious Diseases, Tokyo 208, Japan.


Molecular and Cellular Biology, March 1999, p. 1810-1820, Vol. 19, No. 3
0270-7306/99



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