Signal Transduction Pathways in Development and Immunity: NFκB/Rel Pathways

Abstract

The nuclear factor kappa B (NFκB)/Rel signal transduction pathway is conserved from simple multicellular eukaryotes, such as sponges and insects, to humans and controls a variety of processes involved primarily in immunity and development. The NFκB family of transcription factors includes several structurally related proteins that form dimers, which regulate the expression of numerous genes by binding to specific deoxyribonucleic acid (DNA) sites near these genes. In mammals, the NFκB pathway is important in the control of innate and adaptive immunity, immune cell development, cell proliferation and cell survival. In insects, the NFκB pathway controls the establishment of dorsal–ventral polarity in the early embryo and an antimicrobial response. Activation of NFκB transcription factors occurs via a series of biochemical steps and involves translocation of NFκB from the cytoplasm to the nucleus where it can activate gene expression. Misregulation of the NFκB pathway is also implicated in several human disease states, including many types of cancer and inflammatory diseases.

Key concepts:

  • NFκB and Rel proteins are part of a family of transcription factors whose activity is controlled primarily by subcellular localization.

  • Many extracellular signals can activate a multicomponent signal transduction pathway that leads to nuclear localization of NFκB/Rel proteins where they control the transcription of many important effector genes.

  • NFκB/Rel transcription factors control a number of evolutionarily conserved developmental and immune processes.

  • In Drosophila, NFκB/Rel signalling controls the immune response of flies to fungal and bacterial infections.

  • In vertebrates, NFκB/Rel signalling controls the innate immune response, cell survival and the development of several specific cell types, such as liver cells, immune cells and skin cells.

  • Misregulation of NFκB/Rel activity occurs in a number of human diseases, including several chronic inflammatory diseases and cancers.

Keywords: NF‐kappaB; Rel; Dorsal; transcription factor; immune response

Figure 1.

Generalized structures of the two classes of NFκB proteins. The Rel homology (RH) domain contains sequences important for DNA binding, inhibitor (IκB) binding, dimerization and nuclear localization (N). The C‐terminal halves contain inhibitory ankyrin repeats (the ‘NFκB’ proteins, top) or transactivation sequences (the ‘Rel’ proteins bottom). The top class of NFκB proteins can undergo proteolysis at the indicated region to remove the ankyrin repeat domain and generate an active DNA‐binding protein. See text for more details.

Figure 2.

Comparison of the NFκB signalling pathways in Drosophila and mammals. Shown at the right is the general scheme for activation of the NFκB signalling pathway. Shown at the left and centre are the corresponding components of the various NFκB pathways in Drosophila and mammals. See text for more details.

close

References

Beg AA, Sha WC, Bronson RT, Ghosh S and Baltimore D (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF‐κB. Nature 376: 167–170.

Campbell IK, Gerondakis S, O'Connell K and Wicks IP (2000) Distinct roles for the NFκB1 (p50) and c‐Rel transcription factors in inflammatory arthritis. Journal of Clinical Investigation 105: 1799–1806.

Courtois G and Gilmore TD (2006) Mutations in the NF‐κB signalling pathway: implications for human disease. Oncogene 25: 6831–6843.

Doi TS, Marino MW, Takahashi T et al. (1999) Absence of TNF rescues RelA deficient mice from embryonic lethality. Proceedings of the National Academy of Sciences of the USA 96: 2994–2999.

Gauthier M and Degnan BM (2008) The transcription factor NF‐κB in the demosponge Amphimedon queenslandica: insights on the evolutionary origin of the Rel homology domain. Development Genes and Evolution 21: 23–32.

Howard TD, Paznekas WA, Green ED et al. (1997) Mutations in TWIST, a basic helix‐loop‐helix transcription factor, in Saethre–Chotzen syndrome. Nature Genetics 15: 36–41.

Hu Y, Baud V, Delhase M et al. (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKαsubunit of the IκB kinase. Science 284: 316–320.

Iotsova V, Caamaño J, Loy J et al. (1997) Osteoporosis in mice lacking NFκB1 and NFκB2. Nature Medicine 3: 1285–1289.

Kanegae Y, Taveres AT, Belmonte JCI and Verma IM (1998) Role of Rel/NF‐κB transcription factors during the outgrowth of the vertebrate limb. Nature 392: 611–614.

Klement JF, Rice NR, Car BD et al. (1996) IκB deficiency results in a sustained NFκB response and severe widespread dermatitis in mice. Molecular and Cellular Biology 16: 2341–2349.

Köntgen F, Grumont RJ, Strasser A et al. (1995) Mice lacking the c‐rel proto‐oncogene exhibit defects in lymphocyte proliferation, humoral immunity and interleukin‐2 expression. Genes & Development 9: 1965–1977.

Li Q, Estepa G, Memet S, Israël A and Verma IM (2000) Complete lack of NFκB activity in IKK1 and IKK2 double‐deficient mice: additional defect in neurulation. Genes & Development 14: 1729–1733.

Pasparakis M, Schmidt‐Supprian M and Rajewsky K (2002) IκB kinase signaling is essential for maintenance of mature B cells. Journal of Experimental Medicine 196: 743–752.

Sha WC, Liou H‐C, Tuomanen EI and Baltimore D (1995) Targeted disruption of the p50 subunit of NF‐κB leads to multifocal defects in immune responses. Cell 80: 321–330.

Sullivan JC, Kalaitzidis D, Gilmore TD and Finnerty JR (2007) Rel homology domain‐containing transcription factors in the cnidarian Nematostella vectensis. Development Genes and Evolution 217: 63–72.

Further Reading

Aggarwal K and Silverman N (2008) Positive and negative regulation of the Drosophila immune response. BMB Reports 41: 267–277.

Chen LF and Greene WC (2004) Shaping the nuclear action of NF‐κB. Nature Reviews Molecular and Cellular Biology 5: 392–401.

Ferrandon D, Imler JL, Hetru C and Hoffmann JA (2007) The Drosophila systemic immune response: sensing the signalling during bacterial and fungal infections. Nature Reviews. Immunology 7: 862–874.

Gerondakis S, Grumont R, Gugasyan R et al. (2006) Unravelling the complexities of the NF‐κB signalling pathway using mouse knockout and transgenic models. Oncogene 25: 6781–6799.

Ghosh S (ed.) (2007) Handbook or Transcription Factor NF‐kappaB. Boca Raton, Florida: CRC Press.

Gilmore TD (ed.) (2006) NF‐κB: from basic research to human disease. Oncogene 25(Special issue): 6679–6899.

Gilmore Laboratory Website. http://www.nf‐kb.org. Maintained by the Gilmore Laboratory.

Hayden MS and Ghosh S (2008) Shared principles in NF‐κB signalling. Cell 132: 344–362.

Hayden MS, West AP and Ghosh S (2006) NF‐κB and the immune response. Oncogene 25: 6758–6780.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Gilmore, Thomas D, and Tony Ip, Y(Sep 2009) Signal Transduction Pathways in Development and Immunity: NFκB/Rel Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002332.pub3]