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 , .
BAFF bands to all three receptors
BAFF-R, BCMA and
TACI, whereas APRIL bands to
two of them - BCMA and TACI
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
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) , , .
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 .
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) , .
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 .
In addition, RelB may participate in
BAFF-R-dependent production of Immunoglobulins in the
earliest stages of B-cell maturation . It is shown, that
NF-kB2(p52) may activate transcription of
BAFF forming positive feedback loop .
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)
. 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)  and Prostaglandin-endoperoxide synthase 2 (COX-2)
in TACI-dependent manner , .
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 , , . It is shown, that
NF-kB1(p50) and RelA(p65) may
activate transcription of BAFF forming a positive feedback
In addition, NF-kB1 (p50) may participate in
BAFF-R-dependent production of Ig in the B-cell maturation
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 , . NF-AT1(NFATC2) and
NF-AT2(NFATC1) may activate transcription of
BAFF forming a positive feedback loop . In
addition, these transcription factors may participate in
TACI-dependent stimulation of
COX-2 transcription , .
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
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