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

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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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Figure 1: OTUD7B negatively regulates the non-canonical NF-κB pathway.
Figure 2: OTUD7B negatively regulates TRAF3 degradation by affecting TRAF3 ubiquitination.
Figure 3: OTUD7B inducibly interacts with TRAF3 and is recruited to the receptor complexes.
Figure 4: OTUD7B negatively regulates intestinal lymphoid homeostasis, antibacterial immunity and B-cell responses.

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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.

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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.

Corresponding author

Correspondence to Shao-Cong Sun.

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The authors declare no competing financial interests.

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Hu, H., Brittain, G., Chang, JH. et al. OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature 494, 371–374 (2013). https://doi.org/10.1038/nature11831

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