Abstract
Transforming growth factor-β1 (TGF-β1) regulates inflammation and can inhibit activation of the transcription factor NF-κB in certain cell types. Here we show that the TGF-β-induced signaling protein Smad7 bound to TAB2 and TAB3, which are adaptors that link the kinase TAK1 to 'upstream' regulators in the proinflammatory tumor necrosis factor (TNF) signaling pathway. Smad7 thereby promoted TGF-β-mediated anti-inflammatory effects. The formation of Smad7-TAB2 and Smad7-TAB3 complexes resulted in the suppression of TNF signaling through the adaptors TRAF2, TAB2 and/or TAB3, and TAK1. Furthermore, expression of a transgene encoding Smad7 in mouse skin suppressed inflammation and NF-κB nuclear translocation substantially and disrupted the formation of endogenous TRAF2-TAK1-TAB2 and TRAF2-TAK1-TAB3 complexes. Thus, Smad7 is a critical mediator of TGF-β signals that block proinflammatory TNF signals.
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Acknowledgements
We thank A. Roberts, G. Merlino and A. Hobbie for the critical reading of the manuscript; J.L. Wrana (University of Toronto) for plasmids expressing Smad7; K. Miyazono (University of Tokyo) for adenovirus expressing Smad7; and C.J. Hastie (University of Dundee) for the TAB3-specific antibody S81B. Supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health (X.-J.W.) and the Korea Research Foundation (funded by the Korean Government; KRF-2003-015-C00528 and R08-2003-000-10077-0 to S.H.P).
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S.H., S.L. and C.L. did experimental work and analyzed data; A.G.L. and X.-J.W. developed the K5.Smad7 mice and did the skin inflammation study; Y.S.L., E.-K.L. and S.H.P. did the primary peritoneal macrophage study; S.H.P. participated in study design; S.-J.K. designed and conceptualized the research and supervised the experimental work; and S.H. and S.-J.K. analyzed data and wrote the manuscript.
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Supplementary information
Supplementary Fig. 1
C-terminal region of Smad7 binds to TAB2. (PDF 99 kb)
Supplementary Fig. 2
Smad7 inhibits the activation of NF-κB. (PDF 133 kb)
Supplementary Fig. 3
TGF-β1 inhibits TNF-induced gene expression through Smad7. (PDF 78 kb)
Supplementary Fig. 4
Inhibition of endogenous Smad7 reduces the suppressive effect of TGF-β1 on TNF-induced IKK activity. (PDF 110 kb)
Supplementary Fig. 5
Smad7 does not block the oligomerization of TRAF2 and TRAF5. (PDF 72 kb)
Supplementary Fig. 6
Smad7 does not modulate the ubiquitination of RIP1. (PDF 65 kb)
Supplementary Fig. 7
Smad7 blocks the interaction of TAK1 and TRAF5. (PDF 136 kb)
Supplementary Fig. 8
Smad7C-M3 failed to suppress TRAF2–TAB2- or TRAF2–TAB3-induced IKK activity (PDF 104 kb)
Supplementary Fig. 9
Schematic diagram of crosstalk between TGF-β1 and TNF signaling. (PDF 65 kb)
Supplementary Table
Primer sequences for quantitative RT-PCR. (PDF 45 kb)
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Hong, S., Lim, S., Li, A. et al. Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol 8, 504–513 (2007). https://doi.org/10.1038/ni1451
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DOI: https://doi.org/10.1038/ni1451
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