Non-Canonical NF-κB Signaling Initiated by BAFF Influences B Cell Biology at Multiple Junctures

Abstract

It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the non-canonical pathway involving NF-κB2. During this time a great deal of evidence has been amassed on the ligands and receptors that activate these pathways, the cytoplasmic adapter molecules involved in transducing the signals from receptors to nucleus, and the resulting physiological outcomes within body tissues. In contrast to NF-κB1 signaling, which can be activated by a wide variety of receptors, the NF-κB2 pathway is typically only activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor (TNF) family. Amongst these is B cell activating factor of the TNF family (BAFF) and its receptor BAFFR. Whilst BAFF is produced by many cell types throughout the body, BAFFR expression appears to be restricted to the hematopoietic lineage and B cells in particular. For this reason, the main physiological outcomes of BAFF mediated NF-κB2 activation are confined to B cells. Indeed BAFF mediated NF-κB2 signaling contributes to peripheral B cell survival and maturation as well as playing a role in antibody responses and long term maintenance plasma cells. Thus the importance BAFF and NF-κB2 permeates the entire B cell lifespan and impacts on this important component of the immune system in a variety of ways.

Keywords: B lymphocyte; BAFF; BAFFR; NF-κB2; signaling.

Figure 1

The molecular details of BAFF/BAFFR-mediated activation of NF-κB2 signaling pathway. (A) In the absence of BAFF a complex consisting of TRAF2, TRAF3, and cIAP1/2 facilitate the degradation of NIK, the key kinase involved in activation of NF-κB2 signaling. p100 inhibits NF-κB2 activation by sequestering RelB in the cytoplasm. (B) Following BAFF ligation of BAFFR, TRAF3 is recruited to the receptor and subsequently degraded by the combined actions of TRAF2 and cIAP1/2. Lack of TRAF3 deactivates the TRAF/cIAP complex, releasing NIK from degradation and allowing it to accumulate in the cell. NIK then facilitates degradation of p100 via direct phosphorylation and phosphorylation of IKKα. p100 is subsequently partially degraded and active p52/RelB dimers are able to migrate to the nucleus and initiate NF-κB2 specific gene transcription programs. Refer to Sections “The Absence of BAFFR Ligation: Keeping NF-κB2 Switched Off” and “Turning NF-κB2 on in Response to BAFFR Ligation” of text for further details. Negative control mechanisms which impact on NF-κB2 activation are indicated within dashed boxed, including OTUD7, Act1, IKKα, and nuclear p100, refer to Section “Negative Control Mechanisms Limiting BAFFR Induced NF-κB2” of the text for further details. Small black circles represent ubiquitin, small red circles with P are phosphorylations.

Figure 2

Phenotypic outcomes of B cells in response to BAFF/BAFFR-mediated NF-κB2 activation. Activation of non-canonical NF-κB signaling in response to BAFF contributes to key events throughout the lifespan of a B cell. These include facilitating the survival of immature (Imm) B cells in the periphery and activating transcriptional programs which allow them to mature into follicular and marginal zone (MZ) B cells; contributing to some T-independent immune response; extending the duration of germinal center (GC) reactions; and maintaining long lived plasma cells (PCs) in the bone marrow. Refer to Section “Tissue Responses and Effector Functions: The Outcomes of NF-κB2 Signaling in Response to BAFF” of text for further details.