BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells (original) (raw)
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BAFF-induced NEMO-independent processing of NF-?B2 in maturing B cells
Nat Immunol, 2002
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 NEMOindependent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells.
Immunity, 2006
The maintenance of mature B cells hinges on signals emitted from the BAFF-R cell-surface receptor, but the nature of these signals is incompletely understood. Inhibition of canonical NF-kB transcription factor activity through ablation of the essential scaffold protein NEMO arrests B cell development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway by constitutively active IkB Kinase2 renders B cell survival independent of BAFF-R:BAFF interactions and prevents proapoptotic PKCd nuclear translocation. In addition, canonical NF-kB activity mediates differentiation and proper localization of follicular and marginal zone B cells in the absence of BAFF-R, but not CD19. By replacing BAFF-R signals, constitutive canonical NF-kB signaling, a hallmark of various B cell lymphomas, causes accumulation of resting B cells and promotes their proliferation and survival upon activation, but does not per se induce lymphomagenesis. Therefore, canonical NF-kB activity can substitute for BAFF-R signals in B cell development and pathogenesis.
Alternative pathways of NF-κB activation: A double-edged sword in health and disease
Cytokine & Growth Factor Reviews, 2006
While the classical pathway of NF-kB activation plays critical roles in a wide range of biological processes, the more recently described ''non-canonical'' NF-kB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-kB pathway, based on processing of the nf-kb2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-kB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions.
Immunity, 2004
Rehovot hence, activation of its associated NF-B dimers. Re-Israel cent work has yielded some knowledge of an "alternative" pathway through which NF-B dimers containing p100 are activated. This activation occurs independently Summary of IKK2 or NEMO but is dependent on IKK1. Phosphorylation of p100 upon activation of this pathway leads to The NF-B-inducing kinase (NIK) induces proteolytic limited proteolytic processing in which only the IBprocessing of NF-B2/p100 and, hence, the generation homologous region within p100 is degraded, allowing of NF-B dimers such as p52:RelB but was suggested the resulting p52 fragment to translocate to the nucleus not to signal for the processing of IB. Here, we show in association with some other NF-B proteins (mainly that although the induction of IB degradation in lym-RelB) (Xiao et al., 2001; Senftleben et al., 2001; Solan phocytes by TNF is independent of NIK, its induction et al., 2002; Coope et al., 2002; Claudio et al., 2002; by CD70, CD40 ligand, and BLyS/BAFF, which all also Kayagaki et al., 2002; Dejardin et al., 2002; Yilmaz et al., induce NF-B2/p100 processing, does depend on NIK 2003; Hatada et al., 2003).
Journal of immunology (Baltimore, Md. : 1950), 2015
NF-κB-inducing kinase (NIK) is a primary regulator of the noncanonical NF-κB signaling pathway, which plays a vital role downstream of BAFF, CD40L, lymphotoxin, and other inflammatory mediators. Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs, but the role of NIK in adult animals has not been studied. To address this, we generated mice containing a conditional allele of NIK. Deletion of NIK in adult mice results in decreases in B cell populations in lymph nodes and spleen, similar to what is observed upon blockade of BAFF. Consistent with this, B cells from mice in which NIK is acutely deleted fail to respond to BAFF stimulation in vitro and in vivo. In addition, mice with induced NIK deletion exhibit a significant decrease in germinal center B cells and serum IgA, which is indicative of roles for NIK in additional pathways beyond BAFF signaling. Our conditional NIK-knockout mice may be broadly useful for...
Control of B Lymphocyte Apoptosis by the Transcription Factor NF-κB
Immunity, 2006
B cells maintain homeostasis by balancing cell viability and cell death. B lymphocytes are susceptible to mitochondria-and receptor-initiated cell death at various stages of peripheral differentiation and during immune responses. The inducible transcription factor NF-kB enhances cell viability by activating genes that counteract both cell-death pathways. This review uses characteristic features of NF-kB activation and downregulation to provide insight into the regulation of B cell apoptosis in the periphery. In particular, the temporal patterns of NF-kB induction, differences between Rel family members, and the intersection between canonical and noncanonical signaling pathways in keeping B cells alive are discussed.
Cell reports, 2014
BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.
NF-κB signaling in lymphocytes: a new cast of characters
Journal of Cell Science, 2004
Cell-surface antigen receptors on B and T lymphocytes are complex, multisubunit assemblies that must recruit several accessory proteins and activate multiple signaling pathways in order to illicit a proper immune response. One pathway culminates in the activation of specific protein kinase C (PKC) isoforms, which is necessary for the ultimate activation of the NF-κB transcription factor. Since NF-κB plays a crucial role in the adaptive immune response (e.g. in lymphocyte proliferation and cytokine production), it is important to understand the molecular mechanisms by which NF-κB is regulated. Nevertheless, the connection between PKC activation and NF-κB has remained a mystery that has now been at least partly solved. Recent findings implicate a new scaffolding protein, Bimp3/CARMA1/CARD11, as a key factor in bridging PKC activation with the downstream activation of Bcl10 and MALT1, which ultimately stimulates NF-κB. Since some of these signaling components are lymphocyte specific, t...
The Journal of Immunology, 2012
Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on BAFF for survival. BAFF activates the canonical and noncanonical NF-kB pathways, both of which are required for B cell survival. In this study we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and it specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the Ig hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model of B cell anergy. Furthermore, we found that BAFF stimulation induced Bcl10 association with IkB kinase b, a key component of the canonical NF-kB pathway. Consistently, Bcl10deficient B cells were impaired in BAFF-induced IkBa phosphorylation and formation of nuclear p50/c-Rel complexes. Bcl10deficient B cells also displayed reduced expression of NF-kB2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52/RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-x L , a BAFF-induced NF-kB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-kB activation directly and noncanonical NF-kB activation indirectly. The BAFF-R/Bcl10/NF-kB signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells.