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Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF)

Abstract

Interleukin 17 (IL-17) promotes the expression of chemokines and cytokines via the induction of gene transcription and post-transcriptional stabilization of mRNA. We show here that IL-17 enhanced the stability of chemokine CXCL1 mRNA and other mRNAs through a pathway that involved the adaptor Act1, the adaptors TRAF2 or TRAF5 and the splicing factor SF2 (also known as alternative splicing factor (ASF)). TRAF2 and TRAF5 were necessary for IL-17 to signal the stabilization of CXCL1 mRNA. Furthermore, IL-17 promoted the formation of complexes of TRAF5-TRAF2, Act1 and SF2 (ASF). Overexpression of SF2 (ASF) shortened the half-life of CXCL1 mRNA, whereas depletion of SF2 (ASF) prolonged it. SF2 (ASF) bound chemokine mRNA in unstimulated cells, whereas the SF2 (ASF)-mRNA interaction was much lower after stimulation with IL-17. Our findings define an IL-17-induced signaling pathway that links to the stabilization of selected mRNA species through Act1, TRAF2-TRAF5 and the RNA-binding protein SF2 (ASF).

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Figure 1: Expression of TRAF2 or TRAF5 selectively prolongs the half-life of CXCL1 mRNA.
Figure 2: TRAF2 and TRAF5 are required for IL-17-induced stabilization of CXCL1 mRNA.
Figure 3: IL-17 promotes the interaction of Act1 with TRAF5.
Figure 4: IL-17 induces a complex of TRAF2 or TRAF5 and SF2 (ASF).
Figure 5: SF2 (ASF) promotes enhanced decay of CXCL1 mRNA.
Figure 6: SF2 (ASF) binds CXCL1 mRNA.
Figure 7: IL-17 promotes TRAF5 and SF2 (ASF) function in primary cells.

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References

  1. Ouyang, W., Kolls, J.K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  Google Scholar 

  2. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  Google Scholar 

  3. Kang, Z. et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32, 414–425 (2010).

    Article  CAS  Google Scholar 

  4. Endlich, B., Armstrong, D., Brodsky, J., Novotny, M. & Hamilton, T.A. Distinct temporal patterns of macrophage-inflammatory protein-2 and KC chemokine gene expression in surgical injury. J. Immunol. 168, 3586–3594 (2002).

    Article  CAS  Google Scholar 

  5. Kobayashi, Y. Neutrophil infiltration and chemokines. Crit. Rev. Immunol. 26, 307–316 (2006).

    Article  CAS  Google Scholar 

  6. Charo, I.F. & Ransohoff, R.M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    Article  CAS  Google Scholar 

  7. McAllister, F. et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J. Immunol. 175, 404–412 (2005).

    Article  CAS  Google Scholar 

  8. Witowski, J. et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GROα chemokine from mesothelial cells. J. Immunol. 165, 5814–5821 (2000).

    Article  CAS  Google Scholar 

  9. Hartupee, J., Lu, C., Novotny, M., Li, X. & Hamilton, T.A. IL-17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 4135–4141 (2007).

    Article  CAS  Google Scholar 

  10. Kao, C.Y. et al. Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway. J. Immunol. 175, 6676–6685 (2005).

    Article  CAS  Google Scholar 

  11. Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 8, 247–256 (2007).

    Article  CAS  Google Scholar 

  12. Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).

    Article  CAS  Google Scholar 

  13. Gaffen, S.L. Structure and signalling in the IL-17 receptor family. Nat. Rev. Immunol. 9, 556–567 (2009).

    Article  CAS  Google Scholar 

  14. Ohmori, Y., Fukumoto, S. & Hamilton, T.A. Two structurally distinct κB sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages. J. Immunol. 155, 3593–3600 (1995).

    CAS  PubMed  Google Scholar 

  15. Biswas, R. et al. Regulation of chemokine mRNA stability by lipopolysaccharide and IL-10. J. Immunol. 170, 6202–6208 (2003).

    Article  CAS  Google Scholar 

  16. Hartupee, J. et al. IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6. J. Immunol. 182, 1660–1666 (2009).

    Article  CAS  Google Scholar 

  17. Datta, S. et al. IL-17 Regulates CXCL1 mRNA stability via an AUUUA/tristetraprolin-independent sequence. J. Immunol. 184, 1484–1491 (2010).

    Article  CAS  Google Scholar 

  18. Garneau, N.L., Wilusz, J. & Wilusz, C.J. The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8, 113–126 (2007).

    Article  CAS  Google Scholar 

  19. Anderson, P. Post-transcriptional control of cytokine production. Nat. Immunol. 9, 353–359 (2008).

    Article  CAS  Google Scholar 

  20. Tebo, J.M. et al. IL-1-mediated stabilization of mouse KC mRNA depends on sequences in both 5′ and 3′ untranslated regions. J. Biol. Chem. 275, 12987–12993 (2000).

    Article  CAS  Google Scholar 

  21. Au, P.Y. & Yeh, W.C. Physiological roles and mechanisms of signaling by TRAF2 and TRAF5. Adv. Exp. Med. Biol. 597, 32–47 (2007).

    Article  Google Scholar 

  22. Liu, C. et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal. 2, ra63 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. Jiang, Z., Ninomiya-Tsuji, J., Qian, Y., Matsumoto, K. & Li, X. Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol. Cell. Biol. 22, 7158–7167 (2002).

    Article  CAS  Google Scholar 

  24. Delestienne, N. et al. The splicing factor ASF/SF2 is associated with TIA-1-related/TIA-1-containing ribonucleoproteic complexes and contributes to post-transcriptional repression of gene expression. FEBS J. 277, 2496–2514 (2010).

    Article  CAS  Google Scholar 

  25. Lemaire, R. et al. Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins. Genes Dev. 16, 594–607 (2002).

    Article  CAS  Google Scholar 

  26. Lin, S., Xiao, R., Sun, P., Xu, X. & Fu, X.D. Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation. Mol. Cell 20, 413–425 (2005).

    Article  CAS  Google Scholar 

  27. Cazalla, D. et al. Nuclear export and retention signals in the RS domain of SR proteins. Mol. Cell. Biol. 22, 6871–6882 (2002).

    Article  CAS  Google Scholar 

  28. Huang, Y., Yario, T.A. & Steitz, J.A. A molecular link between SR protein dephosphorylation and mRNA export. Proc. Natl. Acad. Sci. USA 101, 9666–9670 (2004).

    Article  CAS  Google Scholar 

  29. Cáceres, J.F. & Krainer, A.R. Functional analysis of pre-mRNA splicing factor SF2/ASF structural domains. EMBO J. 12, 4715–4726 (1993).

    Article  Google Scholar 

  30. Qin, J. et al. TLR8-mediated NF-κB and JNK activation are TAK1-independent and MEKK3-dependent. J. Biol. Chem. 281, 21013–21021 (2006).

    Article  CAS  Google Scholar 

  31. Chang, S.H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).

    Article  CAS  Google Scholar 

  32. Hamilton, T. et al. Diversity in post-transcriptional control of neutrophil chemoattractant cytokine gene expression. Cytokine 52, 116–122 (2010).

    Article  CAS  Google Scholar 

  33. Tada, K. et al. Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-κB activation and protection from cell death. J. Biol. Chem. 276, 36530–36534 (2001).

    Article  CAS  Google Scholar 

  34. Chen, Z.J. Ubiquitin signalling in the NF-κB pathway. Nat. Cell Biol. 7, 758–765 (2005).

    Article  CAS  Google Scholar 

  35. Chung, J.Y., Lu, M., Yin, Q., Lin, S.C. & Wu, H. Molecular basis for the unique specificity of TRAF6. Adv. Exp. Med. Biol. 597, 122–130 (2007).

    Article  Google Scholar 

  36. Yin, Q., Lamothe, B., Darnay, B.G. & Wu, H. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 48, 10558–10567 (2009).

    Article  CAS  Google Scholar 

  37. Huang, Y. & Steitz, J.A. SRprises along a messenger's journey. Mol. Cell 17, 613–615 (2005).

    Article  CAS  Google Scholar 

  38. Long, J.C. & Caceres, J.F. The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417, 15–27 (2009).

    Article  CAS  Google Scholar 

  39. Sato, H., Hosoda, N. & Maquat, L.E. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol. Cell 29, 255–262 (2008).

    Article  CAS  Google Scholar 

  40. Novotny, M., Datta, S., Biswas, R. & Hamilton, T. Functionally independent AU-rich sequence motifs regulate KC (CXCL1) mRNA. J. Biol. Chem. 280, 30166–30174 (2005).

    Article  CAS  Google Scholar 

  41. Datta, S. et al. Tristetraprolin regulates CXCL1 (KC) mRNA stability. J. Immunol. 180, 2545–2552 (2008).

    Article  CAS  Google Scholar 

  42. Hitti, E. et al. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol. Cell. Biol. 26, 2399–2407 (2006).

    Article  CAS  Google Scholar 

  43. Winzen, R. et al. Distinct domains of AU-rich elements exert different functions in mRNA destabilization and stabilization by p38 mitogen-activated protein kinase or HuR. Mol. Cell. Biol. 24, 4835–4847 (2004).

    Article  CAS  Google Scholar 

  44. Winzen, R. et al. Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets. Mol. Cell. Biol. 27, 8388–8400 (2007).

    Article  CAS  Google Scholar 

  45. Sakon, S. et al. NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J. 22, 3898–3909 (2003).

    Article  CAS  Google Scholar 

  46. Cao, Z., Xiong, J., Takeuchi, M., Kurama, T. & Goeddel, D.V. TRAF6 is a signal transducer for interleukin-1. Nature 383, 443–446 (1996).

    Article  CAS  Google Scholar 

  47. Qian, Y., Zhao, Z., Jiang, Z. & Li, X. Role of NFκB activator Act1 in CD40-mediated signaling in epithelial cells. Proc. Natl. Acad. Sci. USA 99, 9386–9391 (2002).

    Article  CAS  Google Scholar 

  48. Sun, D. & Ding, A. MyD88-mediated stabilization of interferon-γ-induced cytokine and chemokine mRNA. Nat. Immunol. 7, 375–381 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank H. Nakano (Juntendo University School of Medicine) for MEFs deficient in both TRAF2 and TRAF5 and reconstituted TRAF2- and TRAF5-deficient MEFs; and X. Fu (University of California, San Diego) for inducible Tet-Off SF2 (ASF) MEFs. Supported by the US Public Health Service (R01CA039621 to T.H. and R01HL098935 to X.L.), the American Asthma Foundation (X.L.) and the David and Lindsay Morgenthaler Endowment (D.S.).

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M.N., K.B. and C.L. did experiments; D.S. designed, did and interpreted experiments and participated in writing the manuscript; T.H. and X.L. designed and interpreted experiments and participated in writing the manuscript; and all authors reviewed the final version of the manuscript.

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Correspondence to Thomas Hamilton.

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Sun, D., Novotny, M., Bulek, K. et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat Immunol 12, 853–860 (2011). https://doi.org/10.1038/ni.2081

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