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

This article has a correction Sci. Signal. 3(121):er3

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

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

  1. Caini Liu1,*,
  2. Wen Qian1,*,
  3. Youcun Qian1,*,
  4. Natalia V. Giltiay1,
  5. Yi Lu1,
  6. Shadi Swaidani1,
  7. Saurav Misra2,
  8. Li Deng3,
  9. Zhijian J. Chen3,4, and
  10. Xiaoxia Li1,
  1. 1Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44915, USA.
  2. 2Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44915, USA.
  3. 3Department of Molecular Biology at the University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
  4. 4Howard 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.
  1. To whom correspondence should be addressed. E-mail: lix{at}ccf.org
  • * 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 κB. 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.

Citation:

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

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