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IKKi: a novel regulator of Act1, IL-17 signaling and pulmonary inflammation

Cellular & Molecular Immunology volume 8, pages 447–449 (2011)Cite this article

TH17 inflammatory helper cells constitute an important subset of T lymphocytes that secrete the cytokine interleukin 17 (IL-17) and thereby drive inflammation in response to microbial antigens. Dysregulation of TH17 cells, characterized by increased IL-17 production, is a hallmark of many inflammatory and autoimmune diseases such as asthma, multiple sclerosis and rheumatoid arthritis.1 The adaptor molecule and E3 ubiquitin ligase Act1 is a key signaling molecule downstream of the IL-17 receptor (IL-17R) that triggers activation of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, which in turn coordinate the induction of cytokine and chemokine genes that are central to the inflammatory response.2 However, the details of IL-17 signaling and precisely how Act1 is regulated have been poorly understood. In a recent issue of Nature Immunology, Bulek et al. have identified the kinase I kappa B kinase i (IKKi, also known as IKKε) as a critical regulator of Act1 and IL-17 signaling.3

The binding of IL-17 to the heteromeric IL-17 receptor complex (composed of IL-17RA and IL-17RC) leads to the recruitment of Act1 via conserved SEFIR domains present within the receptor complex and Act1. Following the recruitment of Act1, the kinase TAK1 and the E3 ubiquitin ligase TRAF6 are recruited to the receptor and facilitate activation of the IKK complex and the transcription factor NF-κB.2 IL-17 and Act1 also activate the MAPK pathway and promote the stabilization of certain chemokine mRNAs such as CXCL1 mRNA.4 In addition to its function as an adaptor molecule, Act1 functions as a U-box E3 ubiquitin ligase whose activity is essential for IL-17 signaling.5 However, the mechanisms of Act1 activation and downstream signal transmission have been unclear. The recent findings by Bulek et al. describe a novel mechanism of IL-17-induced Act1 activation for MAPK activation and chemokine mRNA stabilization.3 The authors found an IL-17-dependent interaction between Act1 and IKKi concomitant with the phosphorylation of Act1.3 IKKi and the related kinase TBK1 are best known as key signal transducers in innate immune pathways triggered by viral infection that lead to the activation of interferon regulatory factors and Ifn gene induction.6 Using airway epithelial cells from IKKi-deficient mice, the authors demonstrated that IKKi is required for the induction of proinflammatory cytokines and MAPK activation but not NF-κB activation upon IL-17 stimulation.3 The effects of IKKi on inflammatory pathways appear to be specific to IL-17 signaling because no difference in MAPK and NF-κB activation was observed upon tumor-necrosis factor stimulation of airway epithelial cells.

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  1. Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, FL, USA

    Noula Shembade & Edward W Harhaj

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  1. Noula Shembade
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  2. Edward W Harhaj
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Correspondence to Noula Shembade or Edward W Harhaj.

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Shembade, N., Harhaj, E. IKKi: a novel regulator of Act1, IL-17 signaling and pulmonary inflammation. Cell Mol Immunol 8, 447–449 (2011). https://doi.org/10.1038/cmi.2011.44

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