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TRADD interacts with STAT1-α and influences interferon-γ signaling

Nature Immunology volume 5, pages 199–207 (2004)Cite this article

An Erratum to this article was published on 01 March 2004

A Corrigendum to this article was published on 01 March 2004

Abstract

Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is essential in recruiting signaling molecules to the TNFR1 receptor complex. Interferon-γ (IFN-γ) is a potent activator of macrophages and uses signal transducer and activator of transcription 1-α (STAT1-α) for signal transduction. Here we demonstrate that IFN-γ induces the formation of a nuclear-localized TRADD–STAT1-α complex. IFN-γ-mediated STAT1-α phosphorylation was prolonged in cells with reduced TRADD expression. Moreover, we noted an increase in IFN-γ-mediated STAT1-α DNA-binding activity, nuclear presence and transcriptional potential in the TRADD knockdown cells. These data indicate that TRADD may be involved in IFN-γ signaling by forming a complex with STAT1-α within the nucleus and regulating IFN-γ-mediated STAT1-α activation.

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Figure 1: IFN-γ treatment induces TRADD–STAT1-α complex formation.
Figure 2: TRADD and STAT1-α colocalize to the nucleus.
Figure 3: TRADD translocation is independent of STAT1-α activation.
Figure 4: The TRADD N terminus binds STAT1-α.
Figure 5: TRADD affects IFN-γ-mediated STAT1-α activation.
Figure 6: TRADD affects STAT1-α transcriptional activity.
Figure 7: TRADD involvement in IFN-γ-regulated genes.

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References

  1. Locksley, R.M., Killeen, N. & Lenardo, M.J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article  CAS  Google Scholar 

  2. Boehm, U., Klamp, T., Groot, M. & Howard, J.D. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

    Article  CAS  Google Scholar 

  3. Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. & Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  Google Scholar 

  4. Kisseleva, T., Bhattacharya, S., Braunstein, J. & Schindler, C.W. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1–24 (2002).

    Article  CAS  Google Scholar 

  5. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

    Article  CAS  Google Scholar 

  6. Wang, Y., Wu, T.R., Cai, S., Welte, T. & Chin, Y.E. Stat1 as a component of tumor necrosis factor α receptor 1-TRADD signaling complex to inhibit NF-κB activation. Mol. Cell. Biol. 20, 4505–4512 (2000).

    Article  CAS  Google Scholar 

  7. Nguyen, V.T. & Benveniste, E.N. Critical role of TNF-α and NF-κB in IFN-γ-induced CD40 expression in microglia/macrophages. J. Biol. Chem. 277, 13796–13803 (2002).

    Article  CAS  Google Scholar 

  8. Wesemann, D., Dong, Y., O'Keefe, G.M., Nguyen, V.T. & Benveniste, E.N. Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. J. Immunol. 169, 2354–2360 (2002).

    Article  CAS  Google Scholar 

  9. Ramana, C.V. et al. Stat1-independent regulation of gene expression in response to IFN-γ. Proc. Natl. Acad. Sci. USA 98, 6674–6679 (2001).

    Article  CAS  Google Scholar 

  10. Ramana, C.V., Gil, M.P., Schreiber, R.D. & Stark, G.R. Stat1-dependent and -independent pathways in IFN-γ-dependent signaling. Trends Immunol. 23, 96–101 (2002).

    Article  CAS  Google Scholar 

  11. Yasukawa, H. et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 18, 1309–1320 (1999).

    Article  CAS  Google Scholar 

  12. Park, Y.C. et al. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell 101, 777–787 (2000).

    Article  CAS  Google Scholar 

  13. Meyer, T., Marg, A., Lemke, P., Wiesner, B. & Vinkemeier, U. DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1. Genes Dev. 17, 1992–2005 (2003).

    Article  CAS  Google Scholar 

  14. Morgan, M., Thorburn, J., Pandolfi, P.P. & Thorburn, A. Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms. J. Cell Biol. 157, 975–984 (2002).

    Article  CAS  Google Scholar 

  15. Screaton, R.A. et al. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis. Proc. Natl. Acad. Sci. USA 100, 5211–5216 (2003).

    Article  CAS  Google Scholar 

  16. Anest, V. et al. A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression. Nature 423, 659–663 (2003).

    Article  CAS  Google Scholar 

  17. Yamamoto, Y., Verma, U.N., Prajapati, S., Kwak, Y.-T. & Gaynor, R.B. Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression. Nature 423, 655–659 (2003).

    Article  CAS  Google Scholar 

  18. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662–5668 (2002).

    Article  CAS  Google Scholar 

  19. Wu, T.R. et al. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei. J. Biol. Chem. 277, 47572–47580 (2002).

    Article  CAS  Google Scholar 

  20. Zhu, W., Mustelin, T. & David, M. Arginine methylation of STAT1 regulates its dephosphorylation by T cell protein tyrosine phosphatase. J. Biol. Chem. 277, 35787–35790 (2002).

    Article  CAS  Google Scholar 

  21. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    Article  CAS  Google Scholar 

  22. Inada, H. et al. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J. Cell Biol. 155, 415–426 (2001).

    Article  CAS  Google Scholar 

  23. Paludan, S.R. Synergistic action of pro-inflammatory agents: cellular and molecular aspects. J. Leukoc. Biol. 67, 18–25 (2000).

    Article  CAS  Google Scholar 

  24. Nguyen, V.T. & Benveniste, E.N. Involvement of STAT-1α and ets family members in interferon-γ induction of CD40 transcription in macrophages/microglia. J. Biol. Chem. 271, 23674–23684 (2000).

    Article  Google Scholar 

  25. O'Keefe, G.M., Nguyen, V.T., Tang, L.P. & Benveniste, E.N. IFN-γ regulation of class II transactivator promoter IV in macrophages and microglia: involvement of the suppressors of cytokine signaling-1 protein. J. Immunol. 166, 2260–2269 (2001).

    Article  CAS  Google Scholar 

  26. O'Keefe, G.M., Nguyen, V.T. & Benveniste, E.N. Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-β, IL-4, IL-13, and IL-10. Eur. J. Immunol. 29, 1275–1285 (1999).

    Article  CAS  Google Scholar 

  27. Elbashir, S.M., Harborth, J., Weber, K. & Tuschl, T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 26, 199–213 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Z.D. Ma and R. Shah for assistance with the ChIP assay; C. Wilson for assistance with RPA analysis; and S. Frank for comments on the manuscript. The TRADD expression construct was a gift from H. Wu. Supported in part by National Institutes of Health grants NS-36765 and NS-39954 (E.N.B.), and the Medical Scientist Training Program at The University of Alabama at Birmingham and National Institutes of Health Predoctoral Fellowships T32 AI-07051-26 and F30 NS-47051 (D.R.W.).

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  1. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Duane R Wesemann, Hongwei Qin, Natalia Kokorina & Etty N Benveniste

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  1. Duane R Wesemann
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  2. Hongwei Qin
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Correspondence to Etty N Benveniste.

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Wesemann, D., Qin, H., Kokorina, N. et al. TRADD interacts with STAT1-α and influences interferon-γ signaling. Nat Immunol 5, 199–207 (2004). https://doi.org/10.1038/ni1025

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