Apoptosis and survival - APRIL and BAFF signaling

APRIL and BAFF signaling

Tumor necrosis factor (ligand) superfamily members 13 and 13b (APRIL and BAFF) and their receptors - Tumor necrosis factor receptor superfamily members 13C, 17 and 13B (BAFF-R, BCMA and TACI) - play important roles in the B-cell and T-cell arms of the immune system [1], [2]. BAFF bands to all three receptors BAFF-R, BCMA and TACI, whereas APRIL bands to two of them - BCMA and TACI [3].

One of the most important APRIL/ BAFF-induced mechanisms is an activation of Nuclear factors of kappa light polypeptide in B-cells (NF-kB) signaling cascades. Activation and nuclear translocation of NF-kB proteins can occur by one of two pathways: canonical and non-canonical.

Activation of non-canonical NF-kB pathway happens upon BAFF activation of BCMA, TACI and BAFF-R. BCMA and TACI activate TNF receptor-associated factors 2 and 5 (TRAF2 and TRAF5). These TRAFs transit signal to Mitogen-activated protein kinase kinase kinase 14 (NIK) [1], [4], [5].

The exact mechanism of BAFF-R-dependent signaling is unknown, but it is believed, that BAFF-R may repress action of TNF receptor-associated factor 3 (TRAF3) - inhibitor of TRAF2 and NIK [3]. Then, the activated NIK phosphorylates Conserved helix-loop-helix ubiquitous kinase (IKK-alpha), which induces processing of transcription factor NF-kB2 (p100) to NF-kB2(p52) [1], [5].

NF-kB2(p52), along with v-rel reticuloendotheliosis viral oncogene homolog B (RelB), may activate transcription of B-cell CLL/lymphoma 2 (Bcl-2) and/or BCL2-like 1 (Bcl-XL), thus stimulating cell survival [5]. In addition, RelB may participate in BAFF-R-dependent production of Immunoglobulins in the earliest stages of B-cell maturation [6]. It is shown, that NF-kB2(p52) may activate transcription of BAFF forming positive feedback loop [7].

APRIL/ BAFF-induced activation of canonical NF-kB pathway is realized via TNF receptor-associated factor 6 (TRAF6). TRAF6 activates the Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKK gamma)/ IKK alpha/ IKK beta complex, which subsequently phosphorylates NF-kB inhibitor (I-kB). Phosphorylation of I-kB leads to its ubiquitination and degradation. Degradation of I-kB liberates transcription factor NF-kB1(p50) and v-rel reticuloendotheliosis viral oncogene homolog A (RelA(p65)), allowing its rapid translocation from the cytoplasm into the nucleus.

These transcription factors in the form of homo- and heterodimers activate transcription of anti-apoptotic genes Bcl-XL and BCL2-related protein A1 (BFL1) [8]. It is possible that NF-kB1(p50) and RelA(p65) may activate transcription of inflammation proteins Chemokine ligand 4 (MIP-1 beta), Interleukin 10 (IL-10) [9] and Prostaglandin-endoperoxide synthase 2 (COX-2) in TACI-dependent manner [10], [11]. Moreover, these transcription factors may participate in BAFF-dependent stimulation of Fc fragment of IgE low affinity II receptor (CD23) and Complement component receptor 2 (CD1) transcription [12], [13], [14]. It is shown, that NF-kB1(p50) and RelA(p65) may activate transcription of BAFF forming a positive feedback loop [7].

In addition, NF-kB1 (p50) may participate in BAFF-R-dependent production of Ig in the B-cell maturation [8].

TACI activates another signal, different from NF-kB pathway, which is the activation of Nuclear factors of activated T-cells cytoplasmic calcineurin-dependent 2 and 1 (NF-AT1(NFATC2) and NF-AT2(NFATC1)). It is supposed, that TACI activates Calcium modulating ligand (CAML)/ Peptidylprolyl isomerase B (Cyclophilin B)/ Catalytic (A) subunit isoforms of calcineurin (Calcineurin A (catalytic)) cascade [15], [16]. NF-AT1(NFATC2) and NF-AT2(NFATC1) may activate transcription of BAFF forming a positive feedback loop [7]. In addition, these transcription factors may participate in TACI-dependent stimulation of COX-2 transcription [10], [17].

BCMA and/ TACI may activate Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Mitogen-activated protein kinase kinase 4 (MEK4)/ mitogen-activated protein kinase JNK cascade, which may participate, for instance, in antigen presentation and other processes B cell maturation [18], [19].

References:

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