Overview of NFkB signaling

By C. Hooper *

The latest immunology review, giving an overview of NFkB signaling in health and disease.

Contents

1. Introduction to NFkB
2. The NFkB family
3. The NFkB signaling pathways
4. The role of NFkB signaling in disease
5. References


Introduction to NF
kB

NFkB (nuclear factor kappa beta) is a transcription factor that plays important roles in the immune system (Ghosh et al. 1998; Li and Verma 2002; Bonizzi and Karin 2004). NFkB regulates the expression of cytokines, inducible nitric oxide synthase (iNOS), cyclo-oxgenase 2 (COX-2), growth factors, inhibitors of apoptosis and effector enzymes in response to ligation of many receptors involved in immunity including T-cell receptors (TCRs), B-cell receptors (BCRs) and members of the Toll-like receptor/IL-1 receptor super family. NFkB also plays a role in the development and the activity of a number of tissues including the central nervous system (Memet 2006). Moreover, pathological dysregulation of NFkB is linked to inflammatory and autoimmune diseases as well as cancer.


The NF
kB family

In mammals, the NFkB family is composed of five related transcription factors: p50, p52, RelA (p65), c-Rel and RelB (Moynagh 2005; Hoffmann et al., 2006). These transcription factors are related through an N-terminal, 300 amino acid, DNA binding/dimerization domain, called the Rel homology domain (RHD), through which they can form homodimers and heterodimers that bind to 9-10 base pair DNA sites, known as kB sites, in the promoters and enhancer regions of genes, thereby modulating gene expression. RelA, c-Rel and RelB contain C-terminal transcriptional activation domains (TADs), which enable them to activate target gene expression. In contrast, p50 and p52 do not contain C-terminal TADs; therefore, p50 and p52 homodimers repress transcription unless they are bound to a protein containing a TAD, such as RelA, c-Rel or RelB or Bcl-3 (a related transcriptional co-activator). Unlike the other NFkB family members p50 and p52 are derived from larger precursors, p105 and p100, respectively.

NFkB is not synthesized de novo; therefore its transcriptional activity is silenced by interactions with inhibitory IkB proteins present in the cytoplasm. There are currently seven identified IkB family members - IkBa, IkBb, Bcl-3, IkBe, IkBg and the precursor proteins p100 and p105 - which are characterized by the presence of ankyrin repeats.


The NF
kB signaling pathways

There are two signaling pathways leading to the activation of NFkB known as the canonical pathway (or classical) and the non-canonical pathway (or alternative pathway) (Karin 1999; Tergaonkar 2006; Gilmore 2006; Scheidereit 2006). The common regulatory step in both of these cascades is activation of an IkB kinase (IKK) complex consisting of catalytic kinase subunits (IKKa and/or IKKb) and the regulatory non-enzymatic scaffold protein NEMO (NF-kappa B essential modulator also known as IKKg). Activation of NFkB dimers is due to IKK-mediated phosphorylation-induced proteasomal degradation of the IkB inhibitor enabling the active NFkB transcription factor subunits to translocate to the nucleus and induce target gene expression. NFkB activation leads to the expression of the IkBa gene, which consequently sequesters NFkB subunits and terminates transcriptional activity unless a persistent activation signal is present.

In the canonical signaling pathway, binding of ligand to a cell surface receptor such as a member of the the Toll-like receptor superfamily leads to the recruitment of adaptors (such as TRAF) to the cytoplasmic domain of the receptor (Figure 1). These adaptors in turn recruit the IKK complex which leads to phosphorylation and degradation of the IkB inhibitor. The canonical pathway activates NFkB dimers comprising of RelA, c-Rel, RelB and p50.

Figure 1. The canonical pathway

The canonical pathway
The binding of ligand to a receptor leads to the recruitment and activation of an IKK complex comprising IKK alpha and/or IKK beta catalytic subunits and two molcules of NEMO. The IKK complex then phosphorylates IkB leading to degradation by the proteasome. NFkB then translocates to the nucleus to activate target genes regulated by kB sites.


The non-canonical pathway is responsible for the activation of p100/RelB complexes and occurs during the development of lymphoid organs responsible for the generation of B and T lymphocytes (Figure 2). Only a small number of stimuli are known to activate NFkB via this pathway and these factors include lymphotoxin B and B cell activating factor (BAFF). This pathway utilizes an IKK complex that comprises two IKKa subunits, but not NEMO. In the non-canonical pathway, ligand induced activation results in the activation of NFkB-inducing kinase (NIK), which phosphorylates and activates the IKKa complex, which in turn phosphorylates p100 leading to the processing and liberation of the p52/RelB active heterodimer. In contrast to p100, p105 undergoes constitutive cleavage to produce p50, whether p105 can undergo inducible processing remains a contentious issue (Hayden and Ghosh 2004; Moynagh 2005).

Figure 2. The non-canonical pathway

The non-canonical pathway
Receptor binding leads to the activation of NIK, which phosphorylates and activates an IKK alpha complex that in turn phosphorylates the IkB domain of p100 leading to the liberation of p52/RelB. This heterodimer subsequently translocates to the nucleus to activate target genes regulated by kB sites.


The role of NF
kB signaling in disease

Asthma is a chronic inflammatory disorder. The pathogenesis of asthma involves the persistent expression of pro-inflammatory cytokines, chemokines and other such inflammatory mediators. Many of these genes contain the kB site for NFkB within their promoters, suggesting that NFkB plays a vital role in asthma (Yamamoto and Gaynor 2001; Christman et al., 2000). Indeed, increased NFkB activity has been observed in the airways of asthmatic patients (Hart et al., 1998). NFkB is also implicated in inflammatory bowel disease such as Crohn’s disease and ulcerative colitis (Neurath et al., 1998; Schreiber et al., 1998). NFkB activation is evident in biopsies from such patients and treatment of patients with steroids decreases NFkB activity in biopsies as well as reducing the clinical symptoms of disease. Furthermore, NFkB is involved in the pathophysiology of the autoimmune disorder rheumatoid arthritis (RA). NFkB itself is upregulated in RA and cytokines such as TNFa that activate NFkB are elevated in the synovial fluid of patients with RA (Feldmann et al., 1996; Roman-Blas and Jimenez 2006).

In addition to the roles that NFkB plays in inflammatory diseases, constitutive activation of the NFkB pathway is involved in some forms of cancer such as leukemia, lymphoma, colon cancer and ovarian cancer (Rayet and Gelinas 1999).  Mutations that can lead to such tumors include those that inactivate IkB proteins as well as amplifications and rearrangements of genes encoding the NFkB transcription factor subunits. However, more commonly it is thought that changes in the upstream pathways that lead to NFkB activation become deregulated in cancer.


References

Bonizzi G. Karin M. (2004) The two NFkB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280-288.

Christman JW, Sadikot RT, Blackwell TS (2000) The role of nuclear factor-kappa B in pulmonary diseases. Chest. 117:1482–1487

Feldmann M., Brennan F. M., Maini R. N. (1996) Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397-440.

Ghosh S., May M. J., Kopp E. B. (1998) NFkB and Rel proteins: evoluntionary conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225-260.

Gilmore T. D. (2006) Introduction to NFkB: players, pathways, perspectives. Oncogene. 25, 6680-6684.

Hart L. A., Krishnan V. L., Adcock I. M., Barnes P. J., Chung K. F. (1998) Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med.158,1585–1592

Hayden M. S., Ghosh. (2004) Signaling to NFkB. Genes Dev. 18, 2195-2224.

Hoffmann A., Natoli G., Ghosh G. (2006) Transcriptional regulation via the NFkB signaling module. Oncogene. 25, 6706-6716.

Karin M. (1999) How NFkB is activated: the role of the IkB kinase (IKK) complex. Oncogene. 18, 6867-6874.

Li Q., Verma I. M. (2002) NFkB regulation in the immune system. Nat. Rev. Immunol. 2, 725-734.

Memet S. (2006) NFkB functions in the nervous system: From development to disease. Biochem. Pharmacol. 72, 1180-1195.

Moynagh P. N. (2005) The NFkB pathway. J Cell Sci. 118, 4389-4392.

Neurath M. F., Fuss I., Schurmann G., Pettersson S., Arnold K., Muller-Lobeck H., Strober W., Herfarth C., Buschenfelllde K. H. (1998) Cytokine gene transcrition by NF-kappa B family members in patients with inflammatory bowel disease. Ann. N. Y. Acad. Sci. 859, 149-159.

Rayet B., Gelinas C. (1999) Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 18, 6938-6947.

Roman-Blas J. A., Jimenez S. A. (2006) NFkappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage. 14, 839-848.

Scheidereit C (2006) IkB kinase complexes: gateways to NFkB activation and transcription. Oncogene. 25, 6685-6705.

Schreiber S., Nikolaus S., Hampe J. (1998) Activation of nuclear factor kappa B inflammatory bowel disease. Gut. 42, 477-484

Tergaonkar V. (2006) NFkB pathway: A good signaling paradigm and therapeutic target. Int J. Biochem. Cell Biol. 38, 1647-1653.

Yamamoto Y., Gaynor R. B. (2001) Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest.107:135–142


C. Hooper King’s College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry

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