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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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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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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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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DOI: https://doi.org/10.1038/ni.2423
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