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- Title
IL-17 Receptor Signaling Inhibits C/EBPβ by Sequential Phosphorylation of the Regulatory 2 Domain.
- Authors
Fang Shen; Nan Li; Gade, Padmaja; Kalvakolanu, Dhananjaya V.; Weibley, Timothy; Doble, Brad; Woodgett, James R.; Wood, Troy D.; Gaffen, Sarah L.
- 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 kB (NF-kB), CAAT enhancer binding protein δ (C/EBPδ), and C/EBPβ. The adaptor proteins tumor necrosis factor receptor-associated factor 6 (TRAF6) and Act1 are upstream of NF-kB and C/EBPδ, 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-3b-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.
- Publication
Science Signaling, 2009, Vol 2, Issue 59, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.2000066