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The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling

Nature Immunology volume 13, pages 1101–1109 (2012)Cite this article

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An Author Correction to this article was published on 03 July 2020

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Abstract

Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell–specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.

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Figure 1: B cell–specific ablation of Tbk1 results in hyperproduction of IgA and autoantibodies, coupled with nephropathy-like signs.
Figure 2: TBK1 negatively regulates class switching to IgA induced by members of the TNF family.
Figure 3: Class switching to IgA is not affected by deficiency in the receptor for type I interferon or IKKɛ.
Figure 4: TBK1 is a pivotal negative regulator of the noncanonical NF-κB pathway.
Figure 5: The noncanonical NF-κB pathway is required for class switching to IgA.
Figure 6: TBK1 is activated by the TNF family of IgA inducers and negatively regulates the induction of NIK.
Figure 7: TBK1 induces the phosphorylation and degradation of NIK.

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Change history

  • 18 October 2012

    In the version of this article initially published online, the word "isotype" was misspelled in the fourth line of the abstract. The third sentence of the abstract should read, "Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype." The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank Amgen for Map3k14-deficent mice; the Water Eliza Hall Institute of Medical Research for Nfkb2Lym1 mice; S.S. Watowich (University of Texas MD Anderson Cancer Center) for Ifnar1−/− mice; S. Akira (Osaka University) for Flag-tagged IKKɛ (IKKi); G. Cheng (University of California, Los Ageles) for Flag-tagged mouse NIK and mouse NIK(S809A,S812A,S815A) expressed by a pcDNA vector; M. Karin (University of California, San Diego) for hemagglutinin-tagged IKKα and IKKα(SSEE); X. Qin (Sun Yat-Sen University) for packaging vectors psPAX2 and pMD2; C. Wang (Shanghai Institutes for Biological Sciences) for Flag-tagged TBK1 and TBK1(K38A); M.P. Cancro (University of Pennsylvania) for NIH3T3 cell lines; and personnel of the animal facility, flow cytometry, DNA analysis and histology core facilities at MD Anderson Cancer Center for technical assistance. Supported by the US National Institutes of Health (AI057555, AI064639, GM084459 and T32CA009598).

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Jin Jin, Yichuan Xiao, Jae-Hoon Chang, Jiayi Yu, Hongbo Hu, George C Brittain, Mikyoung Chang, Xuhong Cheng & Shao-Cong Sun

  2. St. Vincent's Institute, Fitzroy, Australia

    Robyn Starr

  3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    Shao-Cong Sun

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Contributions

J.J. designed and did the research, prepared the figures, and wrote part of the manuscript; Y.X., J.-H.C., J.Y., H.H., G.C.B., M.C. and X.C. contributed experiments; R.S. contributed reagents; and S.-C.S. designed the research and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Jin, J., Xiao, Y., Chang, JH. et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling. Nat Immunol 13, 1101–1109 (2012). https://doi.org/10.1038/ni.2423

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