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

Hongbo Hu, George C. Brittain, Jae Hoon Chang, Nahum Puebla-Osorio, Jin Jin, Anna Zal, Yichuan Xiao, Xuhong Cheng, Mikyoung Chang, Yang Xin Fu, Tomasz Zal, Chengming Zhu, Shao Cong Sun

Research output: Contribution to journalArticle

113 Scopus citations

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 survival. 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 unknown. 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.

Original languageEnglish (US)
Pages (from-to)371-374
Number of pages4
JournalNature
Volume494
Issue number7437
DOIs
StatePublished - Feb 21 2013

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    Hu, H., Brittain, G. C., Chang, J. H., Puebla-Osorio, N., Jin, J., Zal, A., Xiao, Y., Cheng, X., Chang, M., Fu, Y. X., Zal, T., Zhu, C., & Sun, S. C. (2013). OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3. Nature, 494(7437), 371-374. https://doi.org/10.1038/nature11831