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Sci. Signal., 13 October 2009
Vol. 2, Issue 92, p. ra63
[DOI: 10.1126/scisignal.2000382]

RESEARCH ARTICLES

Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling

Caini Liu1*, Wen Qian1*, Youcun Qian1*, Natalia V. Giltiay1, Yi Lu1, Shadi Swaidani1, Saurav Misra2, Li Deng3, Zhijian J. Chen3,4, and Xiaoxia Li1{dagger}

1 Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44915, USA.
2 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44915, USA.
3 Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
4 Howard Hughes Medical Institute, Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.

* These authors contributed equally to this work.

Abstract: Interleukin-17 (IL-17), a proinflammatory cytokine mainly produced by cells of the T helper 17 (TH17) lineage, is required for host defense against bacterial and fungal infections and plays a critical role in the pathogenesis of inflammatory and autoimmune diseases. Act1 is an essential adaptor molecule in IL-17–mediated signaling and is recruited to the IL-17 receptor (IL-17R) upon IL-17 stimulation through an interaction between its SEFIR domain and that of the IL-17R. Here, we report that Act1 is a U-box E3 ubiquitin ligase and that its activity is essential for IL-17–mediated signaling pathways. Through the use of the Ubc13-Uev1A E2 complex, Act1 mediated the lysine-63–linked ubiquitination of tumor necrosis factor receptor–associated factor 6 (TRAF6), a component of IL-17–mediated signaling. Deletion and point mutations of the Act1 U-box abolished Act1-mediated ubiquitination of TRAF6 and impaired the ability of Act1 to restore IL-17–dependent signaling and expression of target genes in Act1–/– mouse embryonic fibroblasts. We also showed that the lysine-124 residue of TRAF6 was critical for efficient Act1-mediated ubiquitination of TRAF6 and for the ability of TRAF6 to mediate IL-17–induced activation of nuclear factor {kappa}B. Thus, we propose that Act1 mediates IL-17–induced signaling pathways through its E3 ubiquitin ligase activity and that TRAF6 is a critical substrate of Act1, which indicates the importance of protein ubiquitination in the IL-17–dependent inflammatory response.

{dagger} To whom correspondence should be addressed. E-mail: lix{at}ccf.org

Citation: C. Liu, W. Qian, Y. Qian, N. V. Giltiay, Y. Lu, S. Swaidani, S. Misra, L. Deng, Z. J. Chen, X. Li, Act1, a U-box E3 Ubiquitin Ligase for IL-17 Signaling. Sci. Signal. 2, ra63 (2009).

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