Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells

Nature Immunology volume 3, pages 958–965 (2002)Cite this article

Abstract

NF-κB is usually activated by signal-induced, ubiquitin-mediated degradation of its inhibitor, IκB. This process is initiated by phosphorylation of IκB by the IκB kinase (IKK) complex, predominantly by the IKKβ catalytic subunit, and requires the regulatory subunit IKKγ (NEMO). Another activation pathway, with no known physiological inducers, involves ubiquitin-mediated processing of the NF-κB2 inhibitory protein p100 and is dependent on phosphorylation of p100 by IKKα. We show here that B cell–activating factor (BAFF) activates this second pathway and that this requires the BAFF receptor (BAFF-R), the NF-κB–inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: NF-κB1/2 double-deficient B cells fail to progress past the T1 stage and are intrinsically more apoptotic.
Figure 2: BAFF promotes accumulation of IgD+ transitional B cells in in vitro BM cultures from wild-type but not from NF-κB1/2 double-deficient mice.
Figure 3: BAFF function requires BAFF-R, NF-κB2 and NIK.
Figure 4: BAFF induces B220 and Bcl-2 in transitional B cells generated in BM cultures.
Figure 5: BAFF induces processing of NF-κB2 p100 to p52 in mature splenic and immature BM WT B cells.
Figure 6: BAFF induces NF-κB binding and nuclear translocation.
Figure 7: BAFF-induced p100 processing is independent of classical IKK complexes.
Figure 8: p100 processing begins in T1 B cells in vivo.

Similar content being viewed by others

References

  1. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle Cell 109 (Suppl) 81–96 (2002).

    Article  Google Scholar 

  2. Caamano, J. & Hunter C.A. NF-κB family of transcription factors: central regulators of innate and adaptive immune functions Clin. Microbiol. Rev. 15, 414–429 (2002).

    Article  CAS  Google Scholar 

  3. Franzoso, G. et al. Mice deficient in nuclear factor (NF)-κB/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture J. Exp. Med. 187, 147–159 (1998).

    Article  CAS  Google Scholar 

  4. Caamano, J.H. et al. Nuclear factor (NF)-κB2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses J. Exp. Med. 187, 185–196 (1998).

    Article  CAS  Google Scholar 

  5. Gugasyan, R. et al. Rel/NF-κB transcription factors: key mediators of B-cell activation Immunol. Rev. 176, 134–140 (2000).

    Article  CAS  Google Scholar 

  6. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B cell differentiation Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  Google Scholar 

  7. Iotsova, V. et al. Osteopetrosis in mice lacking NF-κB1 and NF-κB2 Nature Med. 3, 1285–1289 (1997).

    Article  CAS  Google Scholar 

  8. Mackay, F. & Mackay, C.R. The role of BAFF in B-cell maturation, T-cell activation and autoimmunity. Trends Immunol. 23, 113–115 (2002).

    Article  CAS  Google Scholar 

  9. Rolink, A.G. & Melchers, F. BAFFled B cells survive and thrive: roles of BAFF in B-cell development. Curr. Opin. Immunol. 14, 266–275 (2002).

    Article  CAS  Google Scholar 

  10. Do, R.K. & Chen-Kiang S. Mechanism of BLyS action in B cell immunity. Cytokine Growth Factor Rev. 13, 19–25 (2002).

    Article  CAS  Google Scholar 

  11. Mackay, F. & Browning, J.L. BAFF: A fundamental survival factor for B cells. Nature Rev. Immunol. 2, 465–475 (2002).

    Article  CAS  Google Scholar 

  12. Thompson, J.S. et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293, 2108–2111 (2001).

    Article  CAS  Google Scholar 

  13. Khare, S.D. et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl. Acad. Sci. USA 97, 3370–3375 (2000).

    Article  CAS  Google Scholar 

  14. Dorner, T. & Putterman C. B cells, BAFF/zTNF4, TACI, and systemic lupus erythematosus. Arthritis Res. 3, 197–199 (2001).

    Article  CAS  Google Scholar 

  15. Groom, J. et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome. J. Clin. Invest. 109, 59–68 (2002).

    Article  CAS  Google Scholar 

  16. Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001).

    Article  CAS  Google Scholar 

  17. Loder, F. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med. 190, 75–89 (1999).

    Article  CAS  Google Scholar 

  18. Khan, W.N. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol. Res. 23, 147–156 (2001).

    Article  CAS  Google Scholar 

  19. Grossmann, M. et al. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl–2 expression. EMBO J. 19, 6351–6360 (2000).

    Article  CAS  Google Scholar 

  20. Rolink, A.G. et al. Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J. Exp. Med. 191, 23–32 (2000).

    Article  CAS  Google Scholar 

  21. Su, T.T. & Rawlings, D.J. Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. J. Immunol. 168, 2101–2110 (2002).

    Article  CAS  Google Scholar 

  22. Cariappa, A. et al. Nuclear factor κB is required for the development of marginal zone B lymphocytes. J. Exp. Med. 192, 1175–1182 (2000).

    Article  CAS  Google Scholar 

  23. Kanno, T. et al. Human T-cell leukemia virus type I Tax-protein-mediated activation of NF-κB from p100 (NF-κB2)-inhibited cytoplasmic reservoirs. Proc. Natl. Acad. Sci. USA 91, 12634–12638 (1994).

    Article  CAS  Google Scholar 

  24. Xiao, G. et al. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Yamada, T. et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-κB-inducing kinase. J. Immunol. 165, 804–812 (2000).

    Article  CAS  Google Scholar 

  27. Kaisho, T. et al. IκB kinase α is essential for mature B cell development and function. J. Exp. Med. 193, 417–426 (2001).

    Article  CAS  Google Scholar 

  28. Do, R.K. et al. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J. Exp. Med. 192, 953–964 (2000).

    Article  CAS  Google Scholar 

  29. Solan, N.J. et al. RelB cellular regulation and transcriptional activity are regulated by p100. J. Biol. Chem. 277, 1405–1418 (2002).

    Article  CAS  Google Scholar 

  30. Yamaoka, S. et al. Complementation cloning of NEMO, a component of the IκB kinase complex essential for NF-κB activation. Cell 93, 1231–1240 (1998).

    Article  CAS  Google Scholar 

  31. Batten, M. et al. BAFF mediates survival of peripheral immature B lymphocytes. J. Exp. Med. 192, 1453–1465 (2000).

    Article  CAS  Google Scholar 

  32. Ellinger-Ziegelbauer, H. et al. Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. J. Biol. Chem. 272, 2668–2674 (1997).

    Article  CAS  Google Scholar 

  33. Dignam, J.D. et al. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11, 1475–1489 (1983).

    Article  CAS  Google Scholar 

  34. Krappmann, D. et al. Different mechanisms control signal-induced degradation and basal turnover of the NF-κB inhibitor IκB α in vivo. EMBO J. 15, 6716–6726 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Sibley and C. Scheidereit for the 70Z/3 and 1.3E2 cells, K. Kelly for critical reading of the manuscript and A. Fauci for continued support.

Author information

Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892-1876, MD, USA

    Estefania Claudio, Keith Brown, Sun Park, Hongshan Wang & Ulrich Siebenlist

Authors
  1. Estefania Claudio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keith Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongshan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrich Siebenlist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Siebenlist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Claudio, E., Brown, K., Park, S. et al. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nat Immunol 3, 958–965 (2002). https://doi.org/10.1038/ni842

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni842

This article is cited by

Search

Advanced search

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