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


Editor's Summary

Acting Out a New Role
Interleukin-17A (IL-17A) is the founding member of a family of proinflammatory cytokines implicated in the development of autoimmunity and the fight against microbial infection. IL-17 signaling, which is mediated by a number of IL-17 receptor (IL-17R) complexes (see the Perspective by Levin), depends on TRAF6, a scaffold protein and E3 ubiquitin ligase, and activates the transcription factor NF-{kappa}B. TRAF6 is recruited to IL-17Rs through another adaptor protein, Act1. Liu et al. now show that Act1 is also a member of the U-box family of E3 enzymes and that its ubiquitin ligase activity is required for IL-17R signaling. In response to IL-17, TRAF6 was recruited to Act1 and underwent Lys63-mediated ubiquitination, a process that was required for the activation of NF-{kappa}B. A mutant form of TRAF6 lacking the residue targeted by ubiquitin failed to support IL-17–mediated activation of NF-{kappa}B in TRAF6-deficient cells. Together, these data identify TRAF6 as a substrate of Act1 and suggest that sequential ubiquitination events regulate IL-17–induced inflammation.

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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Spontaneous Loss of Tolerance of Autoreactive B Cells in Act1-Deficient Rheumatoid Factor Transgenic Mice.
N. V. Giltiay, Y. Lu, J. L. Cullen, T. N. Jorgensen, M. J. Shlomchik, and X. Li (2013)
J. Immunol. 191, 2155-2163
   Abstract »    Full Text »    PDF »
HuR Is Required for IL-17-Induced Act1-Mediated CXCL1 and CXCL5 mRNA Stabilization.
T. Herjan, P. Yao, W. Qian, X. Li, C. Liu, K. Bulek, D. Sun, W.-P. Yang, J. Zhu, A. He, et al. (2013)
J. Immunol. 191, 640-649
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The Deubiquitinase A20 Mediates Feedback Inhibition of Interleukin-17 Receptor Signaling.
A. V. Garg, M. Ahmed, A. N. Vallejo, A. Ma, and S. L. Gaffen (2013)
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IL-17 Receptor Adaptor Protein Act1/CIKS Plays an Evolutionarily Conserved Role in Antiviral Signaling.
G. Ryzhakov, K. Blazek, C. C.-k. Lai, and I. A. Udalova (2012)
J. Immunol. 189, 4852-4858
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TRAF6-Dependent Act1 Phosphorylation by the I{kappa}B Kinase-Related Kinases Suppresses Interleukin-17-Induced NF-{kappa}B Activation.
F. Qu, H. Gao, S. Zhu, P. Shi, Y. Zhang, Y. Liu, B. Jallal, Y. Yao, Y. Shi, and Y. Qian (2012)
Mol. Cell. Biol. 32, 3925-3937
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Cutting Edge: TNF Receptor-Associated Factor 4 Restricts IL-17-Mediated Pathology and Signaling Processes.
J. A. Zepp, C. Liu, W. Qian, L. Wu, M. F. Gulen, Z. Kang, and X. Li (2012)
J. Immunol. 189, 33-37
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CIKS/Act1-Mediated Signaling by IL-17 Cytokines in Context: Implications for How a CIKS Gene Variant May Predispose to Psoriasis.
S. U. Sonder, A. Paun, H.-L. Ha, P. F. Johnson, and U. Siebenlist (2012)
J. Immunol. 188, 5906-5914
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Life before Seventeen: Cloning of the IL-17 Receptor.
S. L. Gaffen (2011)
J. Immunol. 187, 4389-4391
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X. Li and A. M. VanHook (2011)
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A CC' Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17- and IL-25-Induced Inflammation.
C. Liu, S. Swaidani, W. Qian, Z. Kang, P. Sun, Y. Han, C. Wang, M. F. Gulen, W. Yin, C. Zhang, et al. (2011)
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Persistent Stimulation with Interleukin-17 Desensitizes Cells Through SCF{beta}-TrCP-Mediated Degradation of Act1.
P. Shi, S. Zhu, Y. Lin, Y. Liu, Y. Liu, Z. Chen, Y. Shi, and Y. Qian (2011)
Science Signaling 4, ra73
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T Cell-Derived Act1 Is Necessary for IL-25-Mediated Th2 Responses and Allergic Airway Inflammation.
S. Swaidani, K. Bulek, Z. Kang, M. F. Gulen, C. Liu, W. Yin, A. Abbadi, M. Aronica, and X. Li (2011)
J. Immunol. 187, 3155-3164
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J. Biol. Chem. 286, 12881-12890
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A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling.
J. M. Hildebrand, Z. Luo, M. K. Manske, T. Price-Troska, S. C. Ziesmer, W. Lin, B. S. Hostager, S. L. Slager, T. E. Witzig, S. M. Ansell, et al. (2010)
J. Exp. Med. 207, 2569-2579
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Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling.
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J. Exp. Med. 207, 2647-2662
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R. M. Onishi, S. J. Park, W. Hanel, A. W. Ho, A. Maitra, and S. L. Gaffen (2010)
J. Biol. Chem. 285, 32751-32759
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Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Enhances Activation of p38 and ERK MAPKs, Increasing Interleukin-6 Synthesis in Airway Epithelial Cells Exposed to Pseudomonas aeruginosa.
J. Berube, L. Roussel, L. Nattagh, and S. Rousseau (2010)
J. Biol. Chem. 285, 22299-22307
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IL-17RC Is Required for Immune Signaling via an Extended SEF/IL-17R Signaling Domain in the Cytoplasmic Tail.
A. W. Ho, F. Shen, H. R. Conti, N. Patel, E. E. Childs, A. C. Peterson, N. Hernandez-Santos, J. K. Kolls, L. P. Kane, W. Ouyang, et al. (2010)
J. Immunol. 185, 1063-1070
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IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation.
L. Roussel, F. Houle, C. Chan, Y. Yao, J. Berube, R. Olivenstein, J. G. Martin, J. Huot, Q. Hamid, L. Ferri, et al. (2010)
J. Immunol. 184, 4531-4537
   Abstract »    Full Text »    PDF »
IL-17 Receptor Signaling: Ubiquitin Gets In On the Act.
S. D. Levin (2009)
Science Signaling 2, pe64
   Abstract »    Full Text »    PDF »

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