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Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling

Nature Immunology volume 7, pages 139–147 (2006)Cite this article

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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Figure 1: Direct interaction of β-arrestins with TRAF6.
Figure 2: Agonist-stimulated interaction of β-arrestins with TRAF6.
Figure 3: Mapping the regions of interaction between β-arrestins and TRAF6.
Figure 4: The β-arrestins prevent TRAF6 autoubiquitination and oligomerization.
Figure 5: Inhibition of AP-1 and NF-κB activation by β-arrestins.
Figure 6: The β-arrestins regulate cytokine production.
Figure 7: Mice deficient in β-arrestin 2 are more susceptible to endotoxic shock than are wild-type mice.

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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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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,

    Yaya Wang, Yawei Tang, Lin Teng, Yalan Wu, Xiaohui Zhao & Gang Pei

  2. Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China

    Yaya Wang, Yawei Tang, Lin Teng, Yalan Wu, Xiaohui Zhao & Gang Pei

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Correspondence to Gang Pei.

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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)

Supplementary Note (PDF 37 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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