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TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis

Nature Immunology volume 10, pages 965–972 (2009)Cite this article

Abstract

The intensity and duration of immune responses are controlled by many proteins that modulate Toll-like receptor (TLR) signaling. TANK has been linked to positive regulation of the transcription factors IRF3 and NF-κB. Here we demonstrate that TANK is not involved in interferon responses and is a negative regulator of proinflammatory cytokine production induced by TLR signaling. TLR-induced polyubiquitination of the ubiquitin ligase TRAF6 was upregulated in Tank−/− macrophages. Notably, Tank−/− mice spontaneously developed fatal glomerulonephritis owing to deposition of immune complexes. Autoantibody production in Tank−/− mice was abrogated by antibiotic treatment or the absence of interleukin 6 (IL-6) or the adaptor MyD88. Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.

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Figure 1: Enhanced production of immunoglobulins and autoantibodies due to B cell abnormalities in Tank−/− mice.
Figure 2: Development of lethal glomerulonephritis in Tank−/− mice.
Figure 3: Enhanced proinflammatory cytokine production in response to TLR stimulation in Tank−/− mice.
Figure 4: TANK negatively regulates the activation of NF-κB and AP-1 as well as gene expression in response to TLR7 stimulation in macrophages.
Figure 5: TANK controls TRAF6 ubiquitination in response to TLR7 stimulation in macrophages.
Figure 6: Enhanced activation of B cells in Tank−/− mice.
Figure 7: Antibiotic treatment, as well as deficiency of MyD88 or IL-6, ameliorates autoantibody production in Tank−/− mice.

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Acknowledgements

We thank T. Yasui (Osaka University) for Il6−/− mice and plasmids; colleagues in our laboratories; E. Kamada for secretarial assistance; Y. Fujiwara, M. Kumagai and R. Abe for technical assistance; and S. Sato for discussions. Supported by the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and grants from the Ministry of Health, Labour and Welfare in Japan, the Global Center of Excellence Program of Japan, and the US National Institutes of Health (P01 AI070167).

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Author notes

  1. Tatsukata Kawagoe and Osamu Takeuchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Tatsukata Kawagoe, Osamu Takeuchi, Hiroki Kato & Shizuo Akira

  2. Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

    Tatsukata Kawagoe, Osamu Takeuchi, Hiroki Kato & Shizuo Akira

  3. Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan

    Yoshitsugu Takabatake

  4. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan

    Yoshitaka Isaka

  5. Department of Pathology, Hyogo College of Medicine, Hyogo, Japan

    Tohru Tsujimura

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  1. Tatsukata Kawagoe
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Contributions

T.K., O.T. and S.A. designed the research and analyzed data; T.K. generated Tank−/− mice and did most of the experiments; Y.T., Y.I. and T.T. did histological examination of kidneys; H.K. provided advice; and T.K., O.T. and S.A. prepared the manuscript.

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Correspondence to Shizuo Akira.

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Kawagoe, T., Takeuchi, O., Takabatake, Y. et al. TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol 10, 965–972 (2009). https://doi.org/10.1038/ni.1771

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