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TRIM30α negatively regulates TLR-mediated NF-κB activation by targeting TAB2 and TAB3 for degradation

Nature Immunology volume 9, pages 369–377 (2008)Cite this article

Abstract

Toll-like receptor (TLR) signaling is pivotal to innate and adaptive immune responses and must be tightly controlled. The mechanisms of TLR signaling have been the focus of extensive studies. Here we report that the tripartite-motif protein TRIM30α, a RING protein, was induced by TLR agonists and interacted with the TAB2-TAB3-TAK1 adaptor-kinase complex involved in the activation of transcription factor NF-κB. TRIM30α promoted the degradation of TAB2 and TAB3 and inhibited NF-κB activation induced by TLR signaling. In vivo studies showed that transfected or transgenic mice overexpressing TRIM30α were more resistant to endotoxic shock. Consistent with that, in vivo 'knockdown' of TRIM30α mRNA by small interfering RNA impaired lipopolysaccharide-induced tolerance. Finally, expression of TRIM30α depended on NF-κB activation. Our results collectively indicate that TRIM30α negatively regulates TLR-mediated NF-κB activation by targeting degradation of TAB2 and TAB3 by a 'feedback' mechanism.

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Figure 1: TRIM30α is induced by TLR agonists and is specifically expressed in lymphoid tissues.
Figure 2: TRIM30α interacts with TAK1 and TAB2-TaB3.
Figure 3: TRIM30α targets TAB2.
Figure 4: TRIM30α prevents TRAF6 autoubiquitination.
Figure 5: TRIM30α inhibits NF-κB activity.
Figure 6: TRIM30α inhibits IL-6 and TNF production.
Figure 7: TRIM30α contributes to protecting mice from endotoxin shock in vivo.

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References

  1. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  2. Janeway, C.A., Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed Central  Google Scholar 

  3. Yarovinsky, F. et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626–1629 (2005).

    Article  CAS  Google Scholar 

  4. Cook, D.N., Pisetsky, D.S. & Schwartz, D.A. Toll-like receptors in the pathogenesis of human disease. Nat. Immunol. 5, 975–979 (2004).

    Article  CAS  Google Scholar 

  5. Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004).

    Article  CAS  Google Scholar 

  6. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  Google Scholar 

  7. Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).

    Article  CAS  Google Scholar 

  8. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

    Article  CAS  Google Scholar 

  9. Kanayama, A. et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell 15, 535–548 (2004).

    Article  CAS  Google Scholar 

  10. Kishida, S., Sanjo, H., Akira, S., Matsumoto, K. & Ninomiya-Tsuji, J. TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway. Genes Cells 10, 447–454 (2005).

    Article  CAS  PubMed Central  Google Scholar 

  11. Ishitani, T. et al. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 22, 6277–6288 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  12. Nisole, S., Stoye, J.P. & Saib, A. TRIM family proteins: retroviral restriction and antiviral defence. Nat. Rev. Microbiol. 3, 799–808 (2005).

    Article  CAS  Google Scholar 

  13. Sayah, D.M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004).

    Article  CAS  Google Scholar 

  14. Sakuma, R., Noser, J.A., Ohmine, S. & Ikeda, Y. Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins. Nat. Med. 13, 631–635 (2007).

    Article  CAS  Google Scholar 

  15. Gack, M.U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

    Article  CAS  PubMed Central  Google Scholar 

  16. Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  17. Joazeiro, C.A. & Weissman, A.M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).

    Article  CAS  Google Scholar 

  18. Trompouki, E. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424, 793–796 (2003).

    Article  CAS  Google Scholar 

  19. Wang, Y. et al. Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling. Nat. Immunol. 7, 139–147 (2006).

    Article  CAS  Google Scholar 

  20. Elbashir, S.M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  CAS  Google Scholar 

  21. Ge, Q. et al. Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc. Natl. Acad. Sci. USA 101, 8676–8681 (2004).

    Article  CAS  Google Scholar 

  22. Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).

    Article  CAS  Google Scholar 

  23. Takeda, K. & Akira, S. Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14 (2005).

    Article  CAS  Google Scholar 

  24. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

    Article  CAS  Google Scholar 

  25. Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    Article  CAS  Google Scholar 

  26. Kong, H.J. et al. Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J. Immunol. 179, 26–30 (2007).

    Article  CAS  Google Scholar 

  27. Qu, J. et al. Nitric oxide destabilizes pias3 and regulates sumoylation. PLoS ONE 2, e1085 (2007).

    Article  PubMed Central  Google Scholar 

  28. Patarca, R. et al. rpt-1, an intracellular protein from helper/inducer T cells that regulates gene expression of interleukin 2 receptor and human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 85, 2733–2737 (1988).

    Article  CAS  Google Scholar 

  29. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190–198 (2004).

    Article  CAS  Google Scholar 

  30. Husebye, H. et al. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J. 25, 683–692 (2006).

    Article  CAS  PubMed Central  Google Scholar 

  31. Kobayashi, T. et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19, 353–363 (2003).

    Article  CAS  PubMed Central  Google Scholar 

  32. Jiang, Z. et al. Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFκB and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6–TAK1-TAB2-PKR. J. Biol. Chem. 278, 16713–16719 (2003).

    Article  CAS  Google Scholar 

  33. Kawamoto, S. et al. A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett. 470, 263–268 (2000).

    Article  CAS  Google Scholar 

  34. Zeng, R. et al. Characterization of the 3a protein of SARS-associated coronavirus in infected vero E6 cells and SARS patients. J. Mol. Biol. 341, 271–279 (2004).

    Article  Google Scholar 

  35. Hou, W. et al. Pertussis toxin enhances Th1 responses by stimulation of dendritic cells. J. Immunol. 170, 1728–1736 (2003).

    Article  CAS  Google Scholar 

  36. Hill, J.A. et al. Immune modulation by silencing IL-12 production in dendritic cells using small interfering RNA. J. Immunol. 171, 691–696 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Pei, H.B. Shu and C. Wang for comments; and S. Skinner, Y.J. Liu and D. Li for reviewing the manuscript and for suggestions. Vector pCAGGS was a gift from J. Miyazaki (Osaka University); p50-deficient and control wild-type mice were gifts from J. Geng (Shanghai Institutes for Biological Sciences); Flag-tagged TRAF6 expression constructs were gifts from C. Wang (Shanghai Institutes for Biological Sciences); and the ubiquitin plasmid was from G. Pei (Shanghai Institutes for Biological Sciences). Supported by the National Natural Science Foundation of China (30325018, 30530700, 30623003, 30721065 and 90713044), the Chinese Academy of Sciences project (KSCX1-YW-R-43), the National Key Project 973 (2006CB504300 and 2007CB512404), the Technology Commission of Shanghai Municipality (04DZ14902, 04DZ19108, 06DZ22032, 04DZ19112, 05814578 and 07XD14033), the European Union project (SP5B-CT-2006-044161) and the Immunology Division of the E-institutes of Shanghai Universities.

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  1. Mude Shi and Weiwen Deng: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Mude Shi, Weiwen Deng, Enguang Bi, Kairui Mao, Yongyong Ji, Guomei Lin, Xiaodong Wu, Zhiyun Tao, Zhenhu Li, Xinfen Cai & Bing Sun

  2. Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Shuhui Sun

  3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 31003, China

    Charlie Xiang

  4. Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200025, China

    Bing Sun

  5. Immunology Division, E-institutes of Shanghai Universities, Shanghai, 200025, China

    Bing Sun

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Correspondence to Charlie Xiang or Bing Sun.

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Shi, M., Deng, W., Bi, E. et al. TRIM30α negatively regulates TLR-mediated NF-κB activation by targeting TAB2 and TAB3 for degradation. Nat Immunol 9, 369–377 (2008). https://doi.org/10.1038/ni1577

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