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

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.

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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.

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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.

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Correspondence to Ulrich Siebenlist.

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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

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