Research ArticleCytokine Signaling

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

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Science Signaling  24 Feb 2009:
Vol. 2, Issue 59, pp. ra8
DOI: 10.1126/scisignal.2000066

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Getting Negative

Interleukin 17 (IL-17) is a proinflammatory cytokine that is important in mediating immune responses to infectious organisms. In addition, IL-17 plays a critical role in the pathology of autoimmune disorders. Recently, an IL-17–secreting population of T cells, termed T helper 17 (TH17), has been identified as a distinct T cell lineage, stimulating interest in the properties of these cells and the signaling mechanisms of IL-17. IL-17 signals through a receptor complex consisting of IL-17RA and IL-17RC subunits, which have several structural features that distinguish them from other cytokine receptors. Signaling through IL-17RA leads to the activation of the transcription factors NF-κB, C/EBPδ, and C/EBPβ. Although IL-17RA–mediated activation of NF-κB and C/EBPδ is well understood, how IL-17 regulates the activity of C/EBPβ is unclear. Shen et al. used tandem mass spectrometry and other experiments to show that IL-17RA signaling led to the sequential, dual phosphorylation of C/EBPβ. Whereas the first phosphorylation event depended on the activity of extracellular signal–regulated kinase, the second depended on that of glycogen synthase kinase 3β. Phosphorylation of C/EBPβ resulted in repressed expression of IL-17 target genes, the first characterized negative consequence of IL-17R signaling.

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