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

Article metrics

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).

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 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).

  2. 2

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

  3. 3

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

  4. 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).

  5. 5

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

  6. 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).

  7. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 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).

  13. 13

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

  14. 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).

  15. 15

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

  16. 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).

  17. 17

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

  18. 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).

  19. 19

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

  20. 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).

  21. 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).

  22. 22

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

  23. 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).

  24. 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).

  25. 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).

  26. 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).

  27. 27

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

  28. 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).

  29. 29

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

  30. 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).

  31. 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).

  32. 32

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

  33. 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).

  34. 34

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

  35. 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).

  36. 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).

  37. 37

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

  38. 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).

  39. 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).

  40. 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).

  41. 41

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

  42. 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).

  43. 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).

  44. 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).

  45. 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).

  46. 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).

  47. 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).

  48. 48

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

Download references

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.).

Author information

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.

Correspondence to Thomas Hamilton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 (PDF 328 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading