Transcription - NF-kB signaling pathway

NF-kB signaling pathway

The Nuclear factor kappa B (NF-kB) plays a crucial role in immune and inflammatory responses through the regulation of genes encoding pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and inducible enzymes. Transcription factors of the NF-kB family are activated in response to signals that lead to cell growth, differentiation, apoptosis and other events. NF-kB is activated by signals that activate Nuclear factor NF-kappa-B inhibitor kinase (IKK) resulting in the phosphorylation of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB), this targets I-kB for degradation in the proteasome and frees the NF-kB dimer, which then translocates to the nucleus and activates target genes [1].

Tumor necrosis factor (TNF-alpha) binds to one of two distinct receptors, Tumor necrosis factor receptor superfamily, member 1A and 1B (TNF-R1 and TNF-R2), and triggers activation of the canonical NF-kB signaling pathway. Upon ligand binding TNF-R1 recruits TNFRSF1A-associated via death domain (TRADD) which then activates TNF receptor-associated factor 2 (TRAF2), whereas TNF-R2 directly interacts with TRAF2. Subsequent (TRAF2)/ Mitogen-activated protein kinase kinase kinase 14 (NIK(MAP3K14))/ IKK/ I-kB signaling cascade leads to NF-kB activation [2], [3].

The non-canonical pathway of NF-kB activation is utilized in response to the ligation of only certain TNF receptor superfamily members, for example Lymphotoxin beta receptor (LTBR(TNFRSF3)). In the non-canonical pathway, TRAF stimulates NIK, which subsequently activates IKK-alpha by phosphorylation. IKK-alpha promotes the processing of nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NF-kB2 (p100)) from p100 to p52 form. Further processed NF-kB2 is bound to V-rel reticuloendotheliosis viral oncogene homolog B (RelB). NF-kB p52/RelB dimer is translocated into the nucleus to affect gene transcription. The non-canonical pathway is independent on IKK-beta and IKK-gamma [1], [4].

T cell receptor (TCR) and CD28 molecule (CD28) can stimulate NF-KB via Protein kinase C theta (PKC-theta)-dependent pathway [5], [6], [7]. Also CD28 triggers V-akt murine thymoma viral oncogene homolog 1 (AKT)-mediated pathway [6].

Upon binding of Interleukin 1 (IL-1), the Interleukin 1 receptor type I (IL-1RI) associates with Interleukin 1 receptor accessory protein (IL1RAP), forming a functional signaling receptor complex that recruits myeloid differentiation primary response gene 88 (MyD88). This leads to the translocation into this complex of Interleukin-1 receptor-associated kinase (IRAK1/2) together with Toll interacting protein (TOLLIP). IRAK1 binds TNF receptor-associated factor 6 (TRAF6). After dissociation from the receptor complex, IRAK1/TRAF6 induces NIK or Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1))-dependent phosphorylation of IKK [8].

Lipopolysacccharide (LPS) in complex with Lipopolysaccharide binding protein (LBP) binds CD14 molecule (CD14) on the cell membrane. It transfers LPS to lymphocyte antigen 96 (MD-2) and Toll-like receptor 4 (TLR4). TLR4 via binding MyD88 [8] and/or possibly Receptor-interacting serine-threonine kinase 2 (RIPK2) induces NF-kB-activating cascade [9].

References:

1. Liang Y, Zhou Y, Shen P
   NF-kappaB and its regulation on the immune system. Cellular & molecular immunology 2004 Oct;1(5):343-50
2. Ding WX, Yin XM
   Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. Journal of cellular and molecular medicine 2004 Oct-Dec;8(4):445-54
3. Bradley JR
   TNF-mediated inflammatory disease. The Journal of pathology 2008 Jan;214(2):149-60
4. Orange JS, Levy O, Geha RS
   Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunological reviews 2005 Feb;203:21-37
5. Coudronniere N, Villalba M, Englund N, Altman A
   NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta. Proceedings of the National Academy of Sciences of the United States of America 2000 Mar 28;97(7):3394-9
6. Schmitz ML, Bacher S, Dienz O
   NF-kappaB activation pathways induced by T cell costimulation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Dec;17(15):2187-93
7. Li Y, Sedwick CE, Hu J, Altman A
   Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. The Journal of biological chemistry 2005 Jan 14;280(2):1217-23
8. Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R
   TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cellular and molecular life sciences : CMLS 2008 Oct;65(19):2964-78
9. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nu?ez G, Janeway CA, Medzhitov R, Flavell RA
   RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002 Mar 14;416(6877):194-9