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Immunology

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Description

NF-κB, or Nuclear Factor kappa B, is a nuclear transcription factor found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.

Discovery and Characterization

NF-κB was first discovered via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells (Sen and Baltimore, Cell, 1986). NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins (Gilmore, Oncogene 1999).

There are five members in the NF-κB family:

  • NF-κB1
  • NF-κB2
  • RelA (also named p65)
  • RelB
  • c-Rel

While all the members of this family share a REL homology domain in their N-termini, a subfamily including RelA, RelB and c-Rel also have a trans-activation domain in their C-termini. An interesting feature of NF-κB1 and NF-κB2 is that they are synthesized as large precursors, p105 and p100, which undergo processing to generate the second subfamily of NF-κB subunits, p50 and p52, respectively. The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway and involves selective degradation of their C-terminal region containing ankyrin repeats. While the generation of p52 from p100 is a tightly regulated process, p50 is produced from constitutive processing of p105 (Karin and Ben-Neriah, Annu.Rev.Immunol. 2000; Senftleben et al Science 2001).

Activation of NF-kB

It has been recognized for long that many bacterial products can activate NF-κB. In addition, identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB has improved the understanding of how different pathogens activate NF-κB. Moreover, studies identified TLR4 as the receptor for the LPS component of Gram-Negative bacteria. TLRs are key regulators of both innate and adaptive immune Responses . A further study, showed that LPS induces phosphorylation of endogenous p65 (RelA at serine 536) which lead to the loss of IKB inhibitory subunit of NF-κB. (1,2,3)

Unlike RelA, RelB and c-Rel, p50 and p52 do not contain trans-activation domains in their C-termini. Nevertheless, these two NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are repressors of kB transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB or c-Rel (Li and Verma, Nat.Rev.Immunol. 2002). Additionally, the p50 and p52 homodimers also bind to the nuclear protein Bcl-3, forming potent transcriptional activators (Fujita et al, Genes Dev. 1993; Franzoso et al, Nature, 1992; Bours et al, Cell, 1993).

Inhibitiors of kappa B - IkB

In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs, which are characterized by the presence of ankyrin repeats. By virtue of their ankyrin repeat domains, the IκB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in the cytoplasm. IκBs are a family of related proteins that have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain in their C-terminus. Although the IκB family consists of IκBα, IκBβ, IκBγ, IκBε and Bcl-3, the best studied and major IκB protein is IκBα. Of all the IκB members, IκBγ is unique in that it is synthesized from the nf-kb1 gene using an internal promoter, thereby resulting in a protein which is identical to the C-terminus of p105 (Inoue, et all, Cell, 1992). The N-terminal regulatory domains harbor the serines that are phosphorylated in a signal-induced manner. When phosphorylated on these serines (serines 32 and 36), IκB molecules are targeted for ubiquitin-mediated proteosomal degradation. The PEST domain in the C-terminus of these proteins is involved in their constitutive turnover. Due to the presence of ankyrin repeats in their C-termini, p105 and p100 also function as IκB proteins.

Links

Attribution


1. Shehata M, Rel/Nuclear factor-Kappa B apoptosis pathways in human cervical cancer cells, cancer cell international 2005, 5; 10.

2. Lindstrom MT, Bennet R Philip, The role of nuclear factor Kappa B in human labor. Reproduction (2005) 130: 569-581.

3. Buss H, D�rrie A, Shmitz M.Lienhard, Hoffman E, Resh K, Constitutive and Interleukin -1- inducible Phosphoryltion of p65 NF-KB t Serine 536 Is Mediated by Multiple Protein Kinases Including IkB Kinase (IKK)-α ,IKKβ, IKKЄ, TRAF Family Member-associated (TANK)-binding Kinase 1 (TBK1),and an UnKnown Kinase and Couples p65 to TATA-binding Protein-associated Factor II31-mediated Interleukin-8 Transcription, J Biol Chem 2000; VOL.279,NO.53, 55633-55643.

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