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Molecular and Cellular Biology, April 2006, p. 3106-3113, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3106-3113.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Positive and Negative Regulation of the Innate Antiviral Response and Beta Interferon Gene Expression by Deacetylation{dagger}

Inna Nusinzon and Curt M. Horvath*

Departments of Medicine and Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, and Department of Medicine, Evanston Northwestern Healthcare, Evanston, Illinois 60208

Received 1 September 2005/ Returned for modification 8 October 2005/ Accepted 21 January 2006

Beta interferon (IFN-ß) gene expression in response to virus infection relies on the dynamic assembly of a multiprotein enhanceosome complex that is initiated by the activation of two inducible transcription factors, interferon regulatory factor 3 (IRF3) and NF-{kappa}B. Virus or double-stranded RNA-induced activation of IFN-ß gene expression is prevented by the addition of protein deacetylase inhibitors. The isolated IRF-responsive positive regulatory domain was found to require deacetylation for its activity, but IRF3 protein activation leading to its nuclear translocation and DNA binding was not impaired by deacetylase inhibition. In contrast, NF-{kappa}B activity was not affected by deacetylase inhibitors. RNA interference indicated that several deacetylase enzymes, including histone deacetylase 1 (HDAC1), HDAC8, and HDAC6, influence IFN-ß gene expression with opposing effects. While HDAC1 and HDAC8 repress IFN-ß expression, HDAC6 acts as a coactivator essential for enhancer activity. Virus replication is enhanced in HDAC6-depleted cells, demonstrating HDAC6 is an essential component of innate antiviral immunity.

* Corresponding author. Mailing address: Pancoe-ENH Research Pavilion, Northwestern University, 2200 Campus Drive, Evanston, IL 60208. Phone: (847) 491-5530. Fax: (847) 491-4400. E-mail: Horvath{at}northwestern.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2006, p. 3106-3113, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3106-3113.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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