Letter | Published:

OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3

Nature volume 494, pages 371374 (21 February 2013) | Download Citation

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Abstract

The non-canonical NF-κB pathway forms a major arm of NF-κB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival1,2,3. Activation of the non-canonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown1,2. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-κB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyperactivation of non-canonical NF-κB. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. Consequently, the OTUD7B deficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-induced non-canonical NF-κB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.

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Acknowledgements

We thank Z. Chen and P. Evans for expression vectors and J. Browning and Biogen for the anti-LTβR antibody. We also thank the personnel from the flow cytometry, DNA analysis, animal facility, and histology core facilities at The MD Anderson Cancer Center for technical assistance. This study was supported by grants from the National Institutes of Health (AI057555, AI064639 and GM84459 to S.-C.S.; CA137059 to T.Z.; T32CA009598 to G.C.B.) and the Sister Institution Network Fund of MD Anderson Cancer Center.

Author information

Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA

    • Hongbo Hu
    • , George C. Brittain
    • , Jae-Hoon Chang
    • , Nahum Puebla-Osorio
    • , Jin Jin
    • , Anna Zal
    • , Yichuan Xiao
    • , Xuhong Cheng
    • , Mikyoung Chang
    • , Tomasz Zal
    • , Chengming Zhu
    •  & Shao-Cong Sun
  2. Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA

    • Yang-Xin Fu
  3. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA

    • Tomasz Zal
    • , Chengming Zhu
    •  & Shao-Cong Sun

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Contributions

H.H. designed the study, performed experiments, analysed data and wrote part of the manuscript; G.C.B., J.-H.C., N.P.-O., J.J., A.Z., Y. X., X.C. and M.C. contributed to the performance of the experiments, Y.-X.F. contributed critical reagents; C.Z. and T.Z. were involved in the supervision of N.P.-O. and A.Z., respectively, and the discussion of results; and S.-C.S. designed the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shao-Cong Sun.

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DOI

https://doi.org/10.1038/nature11831

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