NF-κB

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NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) is a specific transcription factor that occurs in practically all animal cell types and tissues. By binding to certain regulatory sections of DNA , it can influence the transcription of dependent genes .

meaning

NF-κB is of great importance for the regulation of the immune response , cell proliferation and cell death . The activation of NF-κB is considered critical for the development of inflammation . Finally, NF-κB fulfills important functions in the area of ​​the development of the immune system and the lymphatic organs. The role of NF-κB in other contexts (e.g. in the nervous system ) is the subject of current research.

Due to its diverse functions, NF-κB is also associated with numerous diseases. It is often unclear to what extent the activation of NF-κB actually intervenes causally in the disease process. In some types of cancer , such a role is increasingly seen as likely, so that components of the NF-κB signaling pathway have become important target structures for the development of new drugs.

structure

NF-κB is not a single protein , but five or seven different proteins, the common characteristic of which is a domain of around 300 amino acids , the so-called Rel homology domain. In each case two subunits can bind to one another in different combinations and in this way form dimers . The five and seven subunits of NF-κB currently known in mammals are (alternative designation in brackets):

  1. NF-κB1 (p50 or p105): UniProt P19838
  2. NF-κB2 (p52 or p100): UniProt Q00653
  3. RelA (p65): UniProt Q04206
  4. RelB: UniProt Q01201
  5. c-Rel: UniProt Q04864

The genes for NF-κB1 and NF-κB2 can be used to produce two proteins that differ in length and are named according to their molecular mass . RelA, RelB and c-Rel are also referred to as Rel proteins and, in contrast to NF-κB1 and NF-κB2, contain at least one transactivation domain in addition to the Rel homology domain . Although many different dimers are possible, a combination of a non-Rel protein (NF-κB1 or NF-κB2) and a Rel protein is very often observed; a classic example is the p50 / RelA heterodimer. Such heterodimers have an activating effect because of the transactivation domain of the Rel proteins, while an inhibitory function has been described for dimers without the involvement of Rel proteins (especially for p50 / p50).

functionality

NF-κB can bind to a specific DNA motif of around ten base pairs , the so-called κB motif. The κB motif was detected in numerous regulatory areas in the DNA and is subject to a certain variability, which allows fine regulation with regard to the different NF-κB dimers. The binding of NF-κB to the DNA motif leads in the vast majority of cases to an increased transcription of the genes dependent on it; Depending on the dimer composition, a repression of transcription is observed less often. It is currently assumed that - in terms of magnitude - around 500 different genes are regulated by NF-κB. This includes many cytokines and adhesion molecules that play an important role in regulating the immune system .

Regulation and classification in cellular signaling pathways

In a few cell types, NF-κB is always present in the nucleus and is thus constitutively active (i.e. without the action of external stimuli). This affects, for example, B-lymphocytes and dendritic cells . In most other cell types, however, NF-κB is inactive in the cytoplasm and therefore has no access to the DNA in the cell nucleus . This retention in the cytoplasm is achieved by inhibitory κB proteins (IκBα) that bind to NF-κB and thus deactivate it.

The stimuli that can trigger the activation of NF-κB include growth factors , cytokines (e.g. TNF-α and IL-1β ), but also bacterial and viral antigens (e.g. lipopolysaccharides or double-stranded RNA ) and chemical -physical noxae (e.g .: UV radiation , free radicals ). Such stimulation causes a change in the activity of cellular signaling pathways, which are often mediated by phosphorylation . The MAP kinase pathway is also important among the signaling pathways that are important for NF-κB .

The common end route of the activation of NF-κB consists in the activation of the IκBα-kinase complex (IKK), which phosphorylates the IκBα proteins and thus initiates their ubiquitinylation and degradation by the proteasome . NF-κB molecules are thus released by their inhibitors and can now get into the cell nucleus, where they perform their specific functions. IκBα is quickly resynthesized in order to resume its inhibitory control of NF-κB.

The rapid activation that starts just a few minutes after stimulation is characteristic of NF-κB. This is due to the fact that no time-consuming synthesis of new proteins is necessary for activation, as NF-κB is already in the cytoplasm ready for function and only needs to be released by its specific inhibitor. Another characteristic of NF-κB is its low specificity, because the genes under its control are extremely numerous. These characteristics predestine NF-κB for use in processes that require rapid and comprehensive changes in gene transcription.

In addition to NF-κB, other transcription factors are regulated via their subcellular localization (inactive in the cytoplasm, active in the cell nucleus) and are therefore also referred to as latent cytoplasmic factors .

Examples of genes regulated by NF-κB

Cyclooxygenase-2 (COX-2)

The cyclooxygenase-2 is transcribed reinforced by NF-kB. NF-κB is therefore an intracellular pathway through which TNF-α and IL-1β lead to increased production of prostaglandin E2 .

Similarly, interleukin-6 is transcribed to an increased extent by NF-κB.

Examples of natural inhibitors of NF-κB

Natural inhibitors of NF-κB are z. For example: allicin , genistein , quercetin , curcumin , ginkgo , EGCG and tocotrienols . These substances are the active ingredients of garlic , soy , onions , turmeric (turmeric) , ginkgo, green tea and red palm oil .

For extracts from oregano , coffee , thyme , clove and walnut , a significant reduction in excessive NF-κB values ​​was demonstrated both in vitro and in animal experiments.

Notes and individual references

  1. ^ Pronunciation: En-ef-kappa-be. The name can be attributed to the fact that NF-κB was first described as a protein present in the nucleus of mature B lymphocytes that binds to a DNA motif in the transcription enhancer of the gene for the κ chain of immunoglobulins (Sen and Baltimore 1986 ). Gradually, however, it was shown that NF-κB is present in all cells of the organism; however, the name was retained.
  2. ↑ NF-κB is also known in the fruit fly Drosophila melanogaster . There are three members of the protein family called Dif , Dorsal and Relish .
  3. ↑ Denise Faustman, Miriam Davis: TNF receptor 2 pathway: drug target for autoimmune diseases. In: Nature Reviews Drug Discovery . 9, 2010, pp. 482-493, doi: 10.1038 / nrd3030 .
  4. ↑ S. Rivest, S. Lacroix, L. Vallières, S. Nadeau, J. Zhang, N. Laflamme: How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. In: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. Volume 223, Number 1, January 2000, pp. 22-38, ISSN  0037-9727 . PMID 10632958 . (Review).
  5. ^ NH Nam: Naturally occurring NF-kappaB inhibitors. In: Mini-Rev Med Chem . 6 (8), Aug 2006, pp. 945-951. PMID 16918500 .
  6. ↑ I. Paur, TR Balstad, M. Kolberg, MK Pedersen, LM Austenaa, DR Jacobs, R. Blomhoff: Extract of oregano, coffee, thyme, clove, and walnuts Inhibits NF-kappaB in monocytes and in transgenic reporter mice . In: Cancer Prev Res (Phila) . tape 3 , no. 5 , May 2010, p. 653-663 , doi : 10.1158 / 1940-6207.CAPR-09-0089 , PMID 20424131 .

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