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PNAS 108 (52): 21170-21175

Copyright © 2011 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

I{kappa}B kinase {varepsilon} (IKK{varepsilon}) regulates the balance between type I and type II interferon responses

Sze-Ling Nga, Brad A. Friedmana, Sonja Schmidb, Jason Gertzc, Richard M. Myersc, Benjamin R. tenOeverb,1, and Tom Maniatisa,d,1

aDepartment of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; bDepartment of Microbiology, Mount Sinai School of Medicine, New York, NY 10029; c HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806; and dDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032

Contributed by Tom Maniatis, November 22, 2011 (sent for review November 2, 2011)

Abstract: Virus infection induces the production of type I and type II interferons (IFN-I and IFN-II), cytokines that mediate the antiviral response. IFN-I (IFN-α and IFN-β) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. IFN-II (IFN-{gamma}) induces the homodimerization of STAT1 to form the gamma-activated factor (GAF) complex. ISGF3 and GAF bind specifically to unique regulatory DNA sequences located upstream of IFN-I– and IFN-II–inducible genes, respectively, and activate the expression of distinct sets of antiviral genes. The balance between type I and type II IFN pathways plays a critical role in orchestrating the innate and adaptive immune systems. Here, we show that the phosphorylation of STAT1 by I{kappa}B kinase epsilon (IKK{varepsilon}) inhibits STAT1 homodimerization, and thus assembly of GAF, but does not disrupt ISGF3 formation. Therefore, virus and/or IFN-I activation of IKK{varepsilon} suppresses GAF-dependent transcription and promotes ISGF3-dependent transcription. In the absence of IKK{varepsilon}, GAF-dependent transcription is enhanced at the expense of ISGF3-mediated transcription, rendering cells less resistant to infection. We conclude that IKK{varepsilon} plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways.

Key Words: JAK/STAT • STAT dimerization • IFN-stimulated response element • gamma-activated sequences


Freely available online through the PNAS open access option.

Author contributions: S.-L.N., B.R.t., and T.M. designed research; S.-L.N. performed research; S.S. and R.M.M. contributed new reagents/analytic tools; S.-L.N., B.A.F., J.G., B.R.t., and T.M. analyzed data; and S.-L.N., B.R.t., and T.M. wrote the paper.

The authors declare no conflict of interest.

Data deposition: The sequences reported in this paper have been deposited in the European Nucleotide Archive database (accession nos. ERR033735, ERR033736, ERR033738, ERR033739, ERR033740, and ERR033741) and the Gene Expression Omnibus database, www.ncbi.nlm.nih.gov/geo (accession no. GSE33913).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1119137109/-/DCSupplemental.

1To whom correspondence may be addressed. E-mail: tm2472{at}mail.cumc.columbia.edu or benjamin.tenoever{at}mssm.edu.

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