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Sci. Signal., 24 February 2009
Vol. 2, Issue 59, p. ra8
[DOI: 10.1126/scisignal.2000066]

RESEARCH

IL-17 Receptor Signaling Inhibits C/EBPβ by Sequential Phosphorylation of the Regulatory 2 Domain

Fang Shen1*, Nan Li2, Padmaja Gade3, Dhananjaya V. Kalvakolanu3, Timothy Weibley1, Brad Doble4, James R. Woodgett5, Troy D. Wood2, and Sarah L. Gaffen1,6{dagger}

1 Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
2 Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
3 Department of Microbiology and Immunology, Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
4 Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
5 Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada M5G 1X5.
6 University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, S708 BST, 3500 Terrace Street, Pittsburgh, PA 15261, USA.

* Present address: Genentech Inc., South San Francisco, CA 94080, USA.

Abstract: Interleukin-17 (IL-17), the hallmark cytokine of T helper 17 (TH17) cells, signals through a distinct receptor subclass, yet little is known about the mechanisms involved. IL-17 activates the expression of target genes through the actions of the transcription factors nuclear factor {kappa}B (NF-{kappa}B), CAAT enhancer binding protein {delta} (C/EBP{delta}), and C/EBPβ. The adaptor proteins tumor necrosis factor receptor–associated factor 6 (TRAF6) and Act1 are upstream of NF-{kappa}B and C/EBP{delta}, but the regulation of C/EBPβ remains undefined. Here, we show that IL-17 signaling led to phosphorylation of two sites in the regulatory 2 domain of C/EBPβ in a sequential, interdependent fashion. The first was rapid and dependent on extracellular signal–regulated kinase (ERK), whereas the second was dependent on the activity of glycogen synthase kinase 3β (GSK-3β). These pathways were mediated by distinct subdomains within IL-17 receptor A (IL-17RA). Whereas phosphorylation of threonine 188 (Thr188) was mediated by the previously identified SEF/IL-17R homology domain–Toll-IL-1R–like loop (SEFIR-TILL), phosphorylation of Thr179 occurred through a newly characterized motif located in the distal tail of IL-17RA. Phosphorylated C/EBPβ mediated a negative signal, because blocking ERK and GSK-3β increased expression of IL-17 target genes and a C/EBPβ-Thr188 mutant enhanced activation of a C/EBP-dependent reporter. Overexpression of GSK-3β inhibited IL-17–induced activation of a C/EBP-dependent reporter, and Thr179 of C/EBPβ was not phosphorylated in GSK-3β–deficient cells. Thus, IL-17 triggered the dual phosphorylation of C/EBPβ, which inhibited the expression of proinflammatory genes. This detailed dissection is the first for the IL-17–mediated C/EBP pathway and the first known example of a negative signal mediated by IL-17RA.

{dagger} To whom correspondence should be addressed. E-mail: sig65{at}pitt.edu

Citation: F. Shen, N. Li, P. Gade, D. V. Kalvakolanu, T. Weibley, B. Doble, J. R. Woodgett, T. D. Wood, S. L. Gaffen, IL-17 Receptor Signaling Inhibits C/EBPβ by Sequential Phosphorylation of the Regulatory 2 Domain. Sci. Signal. 2, ra8 (2009).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling.
C. Liu, W. Qian, Y. Qian, N. V. Giltiay, Y. Lu, S. Swaidani, S. Misra, L. Deng, Z. J. Chen, and X. Li (2009)
Science Signaling 2, ra63
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