Abstract
Tumor necrosis factor receptor–associated factor 6 (TRAF6) is critical for mediating Toll-like receptor (TLR)–interleukin 1 receptor (IL-1R) signaling and subsequent activation of NF-κB and AP-1, transcriptional activators of innate immunity. Here we show that β-arrestins, a family of multifunctional proteins, directly interacted with TRAF6 after TLR–IL-1R activation. Formation of the β-arrestin–TRAF6 complex prevented autoubiquitination of TRAF6 and activation of NF-κB and AP-1. Endotoxin-treated β-arrestin 2–deficient mice had higher expression of proinflammatory cytokines and were more susceptible to endotoxic shock. Thus, β-arrestins are essential negative regulators of innate immune activation via TLR–IL-1R signaling.
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Acknowledgements
We thank R.J. Lefkowitz for anti-β-arrestin, MEF cell lines and β-arrestin 2–deficient mice; H. Shu for TRAF1–TRAF6 and TLR3 expression constructs; D. Bohmann for the ubiquitin plasmid; and B. Su for reading the manuscript. Supported by the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
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Supplementary information
Supplementary Fig. 1
Schematic representation of wild-type and deletion mutants of TRAF6 and β-arrestins. (PDF 376 kb)
Supplementary Fig. 2
The TRAF-N domain was required for TRAF6 autoubiquitination and oligomerization. (PDF 296 kb)
Supplementary Fig. 3
IKK activity was augmented in bone marrow-derived macrophages (BMDMs) from Arrb2−/− mice. (PDF 127 kb)
Supplementary Fig. 4
Endogenous TRAF6 autoubiquitination was detected in Arrb−/− MEFs and HeLa cells. (PDF 312 kb)
Supplementary Fig. 5
β-Arrestins regulated cytokine production in HeLa cells. (PDF 236 kb)
Supplementary Fig. 6
Expression of β-arrestins was unaffected in macrophages after LPS stimulation. (PDF 114 kb)
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Wang, Y., Tang, Y., Teng, L. et al. Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling. Nat Immunol 7, 139–147 (2006). https://doi.org/10.1038/ni1294
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DOI: https://doi.org/10.1038/ni1294
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