The NF-κB Family Proteins
NF-κB is a family of closely related transcription factors that includes five genes, including NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA (p65), c-Rel and RelB. These genes generate seven proteins that have a Rel Homology Domain (RHD) in their sequence, which mediates their dimerization, interaction with their specific inhibitors, and DNA binding. There are two types of NF-κB proteins 1）RelA, c-Rel and RelB are synthesized in their mature forms. 2) NF-κB1-p105/p50 and NF-κB2-p100/p52 that are synthesized in a precursor form. The precursor forms (p100 and p105) contain C-terminal ankyrin repeats that are hydrolyzed by the proteasome to produce mature (p50 and p52) proteins. Both p50 and p52 contain a DNA-binding domain, rather than a transactivation domain. NF-κB proteins could be inhibited by IκB proteins which found in the cytoplasm.
Figure 1. The structures of NF-κB signaling proteins. The two subfamilies (Rel and NF-κB) of NF-κB transcription factors are shown at the top. All of them have a conserved DNA-binding/dimerization domain (RHD), which also has sequences crucial for nuclear localization and IκB inhibitor binding. The C-terminal halves of the Rel proteins have transcriptional activation domains (TAD). The C-terminal halves of the NF-κB subfamily proteins have ankyrin repeat-containing inhibitory domains (red bars). The IκB proteins composed of ankyrin repeats, and several (IκBα, IκBβ, IκB ɛ, IκBγ) have two N-terminal serine residues (S) which serves as IKK phosphorylation sites, which signal the ubiquitination and degradation of protein. (NEMO, NF-κB essential modulator; HLH, helix-loop-helix; LZ, leucine zipper; NBD, NEMO binding domain, CC, coiled coil; ZF, zinc finger).
The NF-κB Pathway
NF-κB (nuclear factor kappa-B) is a family of highly conserved transcription factors that regulate many important behaviors in cell, especially inflammatory responses, cellular growth and apoptosis. NF-κB pathway mediates cell function by mediating DNA transcription. The pathway could be activated by a lot of factors including cellular stress, cytokines, free radicals, UV radiation, oxidized LDL (low density lipoproteins), and bacterial or viral infection. When NF-κB is activated, it translocated to the nucleus and binds to specific DNA sequences called response elements. Then RNA polymerase and other coactivators, which recruited by the DNA/NFκB complex transcribe downstream DNA into mRNA, to express proteins. There are two main types of NF-kB signal transduction pathways: canonical (classical) and non-canonical NF-κB pathway.
Figure 2. canonical and non-canonical NF-κB pathway
Canonical Signaling Pathway
In the canonical (or classical) NF-κB pathway, NF-κB dimers such as p50/RelA are maintained in the cytoplasm by interacting with an IκB molecule (usually IκBa). The binding of a ligand to the cell surface receptor recruit adaptors (e.g., TRAFs and RIP) to the cytoplasmic domain of the receptor. In turn, these adaptors often recruit an IKK complex onto the cytoplasmic adaptors. This clustering of molecules at the receptor activates the IKK complex. IKK then phosphorylates IκB at two serine residues, which leads to its K48 ubiquitination and degradation by the proteasome. NF-κB then enters the nucleus to turn on target genes. There is also auto-regulatory process in the canonical pathway. NF-κB activates expression of the IκB a gene that leads to resequestration of the complex in the cytoplasm by the newly synthesized IκB protein.
Non-Canonical Signaling Pathway
The non-canonical (or alternative) pathway is mainly for activation of p100 / RelB complexes during the development B-and T-cell organ. The difference between the canonical pathway and the non-canonical pathway is that only certain receptor signals (Lymphotoxin B (LTb), B-cell activating factor (BAFF), CD40) activate non-canonical pathway. This because it proceeds through an IKK complex that contains two IKKa subunits. In the non-canonical pathway, receptor binding leads to the activation of NIK (A kinase that activates NF-κB). This kinase phosphorylates and activates the IKKa complex, and then phosphorylates two serine residues adjacent to the C-terminal IKB domain of P100 anchor protein, resulting in the partial proteolysis and release of p52 / RelB complex.
NF-κB Proteins as Therapeutic Targets
Some studies have provided evidences for a role of NF-κB in cancer. For example, v-Rel, a viral homologue of c-Rel, is the transforming gene of an avian retrovirus, which is highly oncogenic, and causes aggressive lymphomas and leukemias. v-REL is the oncoprotein of the reticuloendotheliosis (REV-T) retrovirus. Some viral oncoproteins may interact with the IKK complex, and cause NF-κB activation. The Tax oncoprotein from the human T-cell leukemia virus I (HTLV-I) induces NF-κB activity, and activation of NF-κB is required for transformation of rat fibroblasts by HTLV-I tax protein. Furthermore, the Epstein–Barr virus, related to Burkitt’s lymphoma and Hodgkin lymphoma, is also responsible for inducing persistent NF-κB activation. The EBV nuclear antigen-2 (EBNA-2) and latent membrane protein-1 (LMP-1) increase NF-κB transcriptional functions. NF-κB is one of the important regulators of proinflammatory gene expression. It also induces transcription of proinflammatory cytokines, chemokines, adhesion molecules, matrix metalloproteinases and cyclo-oxygenase 2. It’s found that NF-κB is highly activated at sites of inflammation in rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, psoriasis, asthma, etc. Chemotherapeutic agents induce transcription factors p53 and NF-κB simultaneously. p53 induction can activate an apoptotic programme, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. In contrast, NF-κB prevents apoptosis in response to chemotherapeutic agents. Some drugs such as anti-IL-1 and anti-TNFa therapy drugs, anti-inflammatory (e.g. corticosteroids, aspirin) drugs and other non-steroidal anti-inflammatory drugs—used to treat inflammatory diseases have effects on NF-κB activity. Better understanding of the NF-κB signaling pathways will be beneficial for the development of anti-inflammatory drugs. Use of natural product-derived N NF-κB inhibitors (e.g., curcumin, green tea and antioxidants) may contribute to human health.
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