Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.

Caini Liu, Wen Qian, Youcun Qian, Natalia V. Giltiay, Y. Lu, Shadi Swaidani, Saurav Misra, L. Deng, Zhijian J. Chen, Xiaoxia Li

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Abstract

Interleukin-17 (IL-17), a proinflammatory cytokine mainly produced by cells of the T helper 17 (T(H)17) 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 kappaB. 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.

Original languageEnglish (US)
JournalScience Signaling
Volume2
Issue number92
DOIs
StatePublished - Jan 1 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Liu, C., Qian, W., Qian, Y., Giltiay, N. V., Lu, Y., Swaidani, S., Misra, S., Deng, L., Chen, Z. J., & Li, X. (2009). Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Science Signaling, 2(92). https://doi.org/10.1126/scisignal.2000382