Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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



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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.


  1. Dejardin, E. The alternative NF-κB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem. Pharmacol. 72, 1161–1179 (2006)

    Article  CAS  Google Scholar 

  2. Sun, S. C. The noncanonical NF-κB pathway. Immunol. Rev. 246, 125–140 (2012)

    Article  Google Scholar 

  3. Razani, B., Reichardt, A. D. & Cheng, G. Non-canonical NF-κB signaling activation and regulation: principles and perspectives. Immunol. Rev. 244, 44–54 (2011)

    Article  CAS  Google Scholar 

  4. Senftleben, U. et al. Activation of IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001)

    Article  ADS  CAS  Google Scholar 

  5. Xiao, G., Harhaj, E. W. & Sun, S. C. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001)

    Article  CAS  Google Scholar 

  6. Liao, G., Zhang, M., Harhaj, E. W. & Sun, S. C. Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 279, 26243–26250 (2004)

    Article  CAS  Google Scholar 

  7. Vallabhapurapu, S. et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nature Immunol. 9, 1364–1370 (2008)

    Article  CAS  Google Scholar 

  8. Zarnegar, B. J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nature Immunol. 9, 1371–1378 (2008)

    Article  CAS  Google Scholar 

  9. Coornaert, B., Carpentier, I. & Beyaert, R. A20: central gatekeeper in inflammation and immunity. J. Biol. Chem. 284, 8217–8221 (2009)

    Article  CAS  Google Scholar 

  10. Harhaj, E. W. & Dixit, V. M. Regulation of NF-κB by deubiquitinases. Immunol. Rev. 246, 107–124 (2012)

    Article  Google Scholar 

  11. Evans, P. C. et al. Isolation and characterization of two novel A20-like proteins. Biochem. J. 357, 617–623 (2001)

    Article  CAS  Google Scholar 

  12. Lee, E. G. et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000)

    Article  ADS  CAS  Google Scholar 

  13. Häcker, H. et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204–207 (2006)

    Article  ADS  Google Scholar 

  14. Oganesyan, G. et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439, 208–211 (2006)

    Article  ADS  CAS  Google Scholar 

  15. Bremm, A., Freund, S. M. & Komander, D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nature Struct. Mol. Biol. 17, 939–947 (2010)

    Article  CAS  Google Scholar 

  16. Enesa, K. et al. NF-κB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling. J. Biol. Chem. 283, 7036–7045 (2008)

    Article  CAS  Google Scholar 

  17. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol. 10, 159–169 (2010)

    Article  CAS  Google Scholar 

  18. Dohi, T. et al. Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167, 2781–2790 (2001)

    Article  CAS  Google Scholar 

  19. Gommerman, J. L. & Browning, J. L. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nature Rev. Immunol. 3, 642–655 (2003)

    Article  CAS  Google Scholar 

  20. Lorenz, R. G., Chaplin, D. D., McDonald, K. G., McDonough, J. S. & Newberry, R. D. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J. Immunol. 170, 5475–5482 (2003)

    Article  CAS  Google Scholar 

  21. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008)

    Article  ADS  CAS  Google Scholar 

  22. Wang, Y. et al. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010)

    Article  Google Scholar 

  23. Xie, P., Stunz, L. L., Larison, K. D., Yang, B. & Bishop, G. A. Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organs. Immunity 27, 253–267 (2007)

    Article  Google Scholar 

  24. Xu, Y., Cheng, G. & Baltimore, D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 5, 407–415 (1996)

    Article  CAS  Google Scholar 

  25. Xie, P., Kraus, Z. J., Stunz, L. L., Liu, Y. & Bishop, G. A. TNF receptor-associated factor 3 is required for T cell-mediated immunity and TCR/CD28 signaling. J. Immunol. 186, 143–155 (2011)

    Article  CAS  Google Scholar 

  26. Kayagaki, N. et al. DUBA: a deubiquitinase that regulates type I interferon production. Science 318, 1628–1632 (2007)

    Article  ADS  CAS  Google Scholar 

  27. Chang, M., Jin, W. & Sun, S. C. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nature Immunol. 10, 1089–1095 (2009)

    Article  CAS  Google Scholar 

  28. Evans, P. C. et al. A novel type of deubiquitinating enzyme. J. Biol. Chem. 278, 23180–23186 (2003)

    Article  CAS  Google Scholar 

  29. Reiley, W., Zhang, M., Wu, X., Graner, E. & Sun, S.-C. Regulation of the deubiquitinating enzyme CYLD by IκB kinase γ-dependent phosphorylation. Mol. Cell. Biol. 25, 3886–3895 (2005)

    Article  CAS  Google Scholar 

  30. Anders, R. A., Subudhi, S. K., Wang, J., Pfeffer, K. & Fu, Y. X. Contribution of the lymphotoxin β receptor to liver regeneration. J. Immunol. 175, 1295–1300 (2005)

    Article  CAS  Google Scholar 

  31. Lomada, D., Liu, B., Coghlan, L., Hu, Y. & Richie, E. R. Thymus medulla formation and central tolerance are restored in IKKα−/− mice that express an IKKα transgene in keratin 5+ thymic epithelial cells. J. Immunol. 178, 829–837 (2007)

    Article  CAS  Google Scholar 

  32. Morrison, M. D., Reiley, W., Zhang, M. & Sun, S. C. An atypical tumor necrosis factor (TNF) receptor-associated factor-binding motif of B cell-activating factor belonging to the TNF family (BAFF) receptor mediates induction of the noncanonical NF-κB signaling pathway. J. Biol. Chem. 280, 10018–10024 (2005)

    Article  CAS  Google Scholar 

  33. Hassink, G. C. et al. The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep. 10, 755–761 (2009)

    Article  CAS  Google Scholar 

  34. Reiley, W. W. et al. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J. Exp. Med. 204, 1475–1485 (2007)

    Article  CAS  Google Scholar 

  35. Ota, N. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium . Nature Immunol. 12, 941–948 (2011)

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-20 and Supplementary Table 1. (PDF 8125 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing