Pathway Map Details

Apoptosis and survival_APRIL and BAFF signaling



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NF-kB p50/p50, COX-2, MIP-1-beta, NIK(MAP3K14), TRAF6, CD21, NF-AT2(NFATC1), RelA (p65), MEKK1(MAP3K1), NF-kB2 (p52), APRIL(TNFSF13), NF-AT1(NFATC2), BAFF-R, IKK-alpha, Bcl-XL, Calcineurin A (catalytic), TRAF3, IKK-gamma, CAML, TRAF5, NF-kB p50/p65, IKK-beta, BFL1, NF-kB1, IKK (cat), BAFF(TNFSF13B), IL-10, Cyclophilin B, MEK4(MAP2K4), CD23, BCMA(TNFRSF17), JNK(MAPK8-10), NF-kB2 (p100), Bcl-2, TACI(TNFRSF13B), RelB, TRAF2, I-kB

Description:

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 ) [4], [5], [1].

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) [5], [1].

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 [17], [10].

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:

  1. Bossen C, Schneider P
    BAFF, APRIL and their receptors: structure, function and signaling. Seminars in immunology 2006 Oct;18(5):263-75
  2. Mackay F, Leung H
    The role of the BAFF/APRIL system on T cell function. Seminars in immunology 2006 Oct;18(5):284-9
  3. Haiat S, Billard C, Quiney C, Ajchenbaum-Cymbalista F, Kolb JP
    Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia. Immunology 2006 Jul;118(3):281-92
  4. Shu HB, Johnson H
    B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1. Proceedings of the National Academy of Sciences of the United States of America 2000 Aug 1;97(16):9156-61
  5. Claudio E, Brown K, Park S, Wang H, Siebenlist U
    BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nature immunology 2002 Oct;3(10):958-65
  6. Bhattacharya D, Lee DU, Sha WC
    Regulation of Ig class switch recombination by NF-kappaB: retroviral expression of RelB in activated B cells inhibits switching to IgG1, but not to IgE. International immunology 2002 Sep;14(9):983-91
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    Constitutive NF-{kappa}B and NFAT Activation Leads to Stimulation of The BLyS Survival Pathway in Aggressive B Cell Lymphomas. Blood 2006 Feb 23;
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    NF-kappa B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-kappa B2 p100 to p52 in quiescent mature B cells. Journal of immunology (Baltimore, Md. : 1950) 2003 Jul 15;171(2):761-8
  9. Xu LG, Wu M, Hu J, Zhai Z, Shu HB
    Identification of downstream genes up-regulated by the tumor necrosis factor family member TALL-1. Journal of leukocyte biology 2002 Aug;72(2):410-6
  10. Mongini PK, Inman JK, Han H, Fattah RJ, Abramson SB, Attur M
    APRIL and BAFF promote increased viability of replicating human B2 cells via mechanism involving cyclooxygenase 2. Journal of immunology (Baltimore, Md. : 1950) 2006 Jun 1;176(11):6736-51
  11. Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB
    Indirubin enhances TNF-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. The Journal of biological chemistry 2006 Jun 19;
  12. Tinnell SB, Jacobs-Helber SM, Sterneck E, Sawyer ST, Conrad DH
    STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production. International immunology 1998 Oct;10(10):1529-38
  13. Tolnay M, Vereshchagina LA, Tsokos GC
    NF-kappaB regulates the expression of the human complement receptor 2 gene. Journal of immunology (Baltimore, Md. : 1950) 2002 Dec 1;169(11):6236-43
  14. Gorelik L, Cutler AH, Thill G, Miklasz SD, Shea DE, Ambrose C, Bixler SA, Su L, Scott ML, Kalled SL
    Cutting edge: BAFF regulates CD21/35 and CD23 expression independent of its B cell survival function. Journal of immunology (Baltimore, Md. : 1950) 2004 Jan 15;172(2):762-6
  15. Holloway MP, Bram RJ
    A hydrophobic domain of Ca2+-modulating cyclophilin ligand modulates calcium influx signaling in T lymphocytes. The Journal of biological chemistry 1996 Apr 12;271(15):8549-52
  16. von Bulow GU, Bram RJ
    NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science 1997 Oct 3;278(5335):138-41
  17. Horsley V, Pavlath GK
    NFAT: ubiquitous regulator of cell differentiation and adaptation. The Journal of cell biology 2002 Mar 4;156(5):771-4
  18. Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J, Devergne O, Tsapis A
    TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Journal of immunology (Baltimore, Md. : 1950) 2000 Aug 1;165(3):1322-30
  19. Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M, Theill LE, Colombero A, Solovyev I, Lee F, McCabe S, Elliott R, Miner K, Hawkins N, Guo J, Stolina M, Yu G, Wang J, Delaney J, Meng SY, Boyle WJ, Hsu H
    TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. The Journal of experimental medicine 2000 Jul 3;192(1):137-43