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First published online July 12, 2005
doi: 10.1242/10.1242/jcs.02445

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Early growth response proteins EGR-4 and EGR-3 interact with immune inflammatory mediators NF-B p50 and p65

Gerhard D. Wieland^1,*, Nina Nehmann^1,*, Doreen Müller¹, Hermann Eibel², Ulrich Siebenlist³, Jürgen Sühnel⁴, Peter F. Zipfel¹ and Christine Skerka^1,

¹ Department of Infection Biology, Leibniz-Institute for Natural Products, Research and Infection Biology, Hans-Knoell-Institute, Butenbergstrasse 11a, 07745 Jena, Germany
² Research Group for Rheumatology, Albert-Ludwig-University, Hugstetter Strasse 55, 79106 Freiburg, Germany
³ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20892, USA
⁴ Biocomputing Group, Institute of Molecular Biotechnology, Beutenbergstrasse 11, 07745 Jena, Germany

Author for correspondence (e-mail: christine.skerka{at}hki-jena.de)

Accepted 19 April 2005

Here, we characterize the basis for the T-cell-specific activity of the human zinc-finger protein early growth response factor 4 (EGR-4). A yeast two-hybrid screen showed interaction of EGR-4 with NF-B p50. Using recombinant proteins, stable physical complex formation was confirmed for EGR-4 and EGR-3 with p50 and with p65 using glutathione-S-transferase pull-down assays and surface-plasmon-resonance and peptide-spot analyses. In vivo interaction of EGR-4 and EGR-3 with NF-B p65 was demonstrated by immunoprecipitation experiments and fluorescence-resonance-energy transfer (FRET) analysis showing interaction in the nucleus of transfected Jurkat T cells. In transfection assays, EGR-p50 complexes were transcriptionally inactive and EGR-p65 complexes strongly activated transcription of the promoters of the human genes encoding the cytokines interleukin 2, tissue necrosis factor and ICAM-1. The EGR-p65 complexes increased reporter-gene activity about 100-fold and thus exceeded the transcriptional activities of the p65 homodimer and the p65/p50 heterodimers. The major interaction domain for p65 was localized within the third zinc finger of EGR-4 using deletion mutants for pull-down assays and peptide-spot assays. By computer modeling, this interaction domain was localized to an -helical region and shown to have the central amino acids surface exposed and thus accessible for interaction. In summary, in T cells, the two zinc-finger proteins EGR-4 and EGR-3 interact with the specific nuclear mediator NF-B and control transcription of genes encoding inflammatory cytokines.

Key words: EGR, NF-B, IL-2, TNF-, ICAM-1

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