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Mechanism of NF-κB action. In this figure, the NF-κB heterodimer between Rel and p50 proteins is used as an example. While in an inactivated state, NF-κB is located in the cytosol complexed with the inhibitory protein IκBα. Through the intermediacy of integral membrane receptors, a variety of extracellular signals can activate the enzyme IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα protein, which results in ubiquitination, dissociation of IκBα from NF-κB, and eventual degradation of IκBα by the proteosome. The activated NF-κB is then translocated into the nucleus where it binds to specific sequences of DNA called response elements (RE). The DNA/NF-κB complex then recruits other proteins such as coactivators and RNA polymerase, which transcribe downstream DNA into mRNA, which, in turn, is translated into protein, which results in a change of cell function.[1][2][3]
Schematic diagram of NF-κB protein structure. There are two structural classes of NF-κB proteins: class I (top) and class II (bottom). Both classes of proteins contain a N-terminal DNA-binding domain (DBD), which also serves as a dimerization interface to other NF-κB transcription factors and in addition binds to the inhibitory IκBα protein. The C-terminus of class I proteins contains a number of ankyrin repeats and has transrepression activity. In contrast, the C-terminus of class II proteins has a transactivation function.[1][2][3]

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens.[1][2][3][4][5] NF-κB plays a key role in regulating the immune response to infection. Conversely, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.[6]

Contents

Discovery

NF-κB was first discovered in the lab of Nobel Prize laureate David Baltimore via its interaction with an 11-base pair sequence in the immunoglobulin light-chain enhancer in B cells.[7]

Structure

All proteins of the NF-κB family share a Rel homology domain in their N-terminus. A subfamily of NF-κB proteins, including RelA, RelB, and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, p105, and p100, which undergo processing to generate the mature 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. Whereas the generation of p52 from p100 is a tightly-regulated process, p50 is produced from constitutive processing of p105.[8][9]

Members

NF-κB family members share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins.[1]

There are five proteins in the mammalian NF-κB family:[10]

Class Protein Aliases Gene
Class I NF-κB1 p105 → p50 NFKB1
NF-κB2 p100 → p52 NFKB2
Class II RelA p65 RELA
RelB RELB
c-Rel REL

Below are the five human NF-κB family members:

NFKB1
1SVC.png
Top view of the crystallographic structure (PDB 1SVC) of a homodimer of the NFKB1 protein (green and magenta) bound to DNA (brown).
Identifiers
Symbol NFKB1
Entrez 4790
HUGO 7794
OMIM 164011
RefSeq NM_003998
UniProt P19838
Other data
Locus Chr. 4 q24
RELA
2RAM.png
Side view of the crystallographic structure (PDB 2RAM) of a homodimer of the RELA protein (green and magenta) bound to DNA (brown).
Identifiers
Symbol RELA
Entrez 5970
HUGO 9955
OMIM 164014
RefSeq NM_021975
UniProt Q04206
Other data
Locus Chr. 11 q13


NFKB2
Identifiers
Symbol NFKB2
Entrez 4791
HUGO 7795
OMIM 164012
RefSeq NM_002502
UniProt Q00653
Other data
Locus Chr. 10 q24
RELB
Identifiers
Symbol RELB
Entrez 5971
HUGO 9956
OMIM 604758
RefSeq NM_006509
UniProt Q01201
Other data
Locus Chr. 19 q13.2-19q13
REL
Identifiers
Symbol REL
Entrez 5966
HUGO 9954
OMIM 164910
RefSeq NM_002908
UniProt Q04864
Other data
Locus Chr. 2 p13-p12


In addition, there are NF-κB proteins in invertebrates, such as the fruit fly Drosophila, sea urchins, sea anemones, and sponges.[11]

Activation

Part of NF-κB's importance in regulating cellular responses is that it belongs to the category of "rapid-acting" primary transcription factors, i.e., transcription factors that are present in cells in an inactive state and do not require new protein synthesis to be activated (other members of this family include transcription factors such as c-Jun, STATs, and nuclear hormone receptors). This allows NF-κB to act as a "first responder" to harmful cellular stimuli. Stimulation of a wide variety of cell-surface receptors, such as RANK, TNFR, leads directly to NF-κB activation and fairly rapid changes in gene expression.[1]

Many bacterial products can activate NF-κB. The identification of Toll-like receptors (TLRs) as specific pattern recognition molecules and the finding that stimulation of TLRs leads to activation of NF-κB improved our understanding of how different pathogens activate NF-κB. For example, studies have identified TLR4 as the receptor for the LPS component of Gram-Negative bacteria.[12] TLRs are key regulators of both innate and adaptive immune responses.[13]

Unlike RelA, RelB, and c-Rel, the p50 and p52 NF-κB subunits do not contain transactivation domains in their C terminal halves. Nevertheless, the p50 and p52 NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are, in general, repressors of κB site transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with RelA, RelB, or c-Rel.[14] In addition, p50 and p52 homodimers also bind to the nuclear protein Bcl-3, and such complexes can function as transcriptional activators.[15][16][17]

Inhibition

In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IκBs (Inhibitor of κB), which are proteins that contain multiple copies of a sequence called 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 an inactive state in the cytoplasm.[18]

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 near 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. Due to the presence of ankyrin repeats in their C-terminal halves, p105 and p100 also function as IκB proteins. 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 that is identical to the C-terminal half of p105.[19] The c-terminal half of p100, that is often referred to as IκBδ, also functions as an inhibitor.[20][21] IκBδ degradation in response to developmental stimuli, such as those transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway.[20][22]

Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKK alpha and IKK beta subunits and a "master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IκB inhibitor molecules are modified by a process called ubiquitination, which then leads them to be degraded by a cell structure called the proteasome.

With the degradation of the IκB inhibitor, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. NF-κB turns on expression of its own repressor, IκBα. The newly synthesized IκBα then re-inhibits NF-κB and, thus, forms an auto feedback loop, which results in oscillating levels of NF-κB activity.[23] In addition, several viruses, including the AIDS virus HIV, have binding sites for NF-κB that controls the expression of viral genes, which in turn contribute to viral replication or viral pathogenicity. In the case of HIV-1, activation of NF-κB may, at least in part, be involved in activation of the virus from a latent, inactive state.[24] YopJ is a factor secreted by Yersinia pestis, the causative agent of plague, that prevents the ubiquitination of IκB. This causes this pathogen to effectively inhibit the NF-κB pathway and thus block the immune response of a human infected with Yersinia.[25]

The non-canonical NF-κB signaling

A select set of cell-differentiating or developmental stimuli, such as lymphotoxin-α, BAFF or RANKL, activate the non-canonical NF-κB pathway to induce NF-κB/RelB:p52 dimer in the nucleus. In this pathway, activation of the NF-κB inducing kinase (NIK) upon receptor ligation led to the phosphorylation and subsequent proteasomal processing of the NF-κB2 precursor protein p100 into mature p52 subunit in a IKK1/IKKa dependent manner. Then p52 dimerizes with RelB to appear as a nuclear RelB:p52 DNA binding activity and regulate a distinct class of genes.[26] In contrast to the canonical signaling that relies upon NEMO-IKK2 mediated degradation of IκBα, -β, -ε, the non-canonical signaling critically depends on NIK mediated processing of p100 into p52. Given their distinct regulations, these two pathways were thought to be independent of each other. However, recent analyses revealed that synthesis of the constituents of the non-canonical pathway, viz RelB and p52, is controlled by the canonical IKK2-IκB-RelA:p50 signaling.[27] Moreover, generation of the canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are also mechanistically interlinked.[27] These analyses suggest that an integrated NF-κB system network underlies activation of both RelA and RelB containing dimer and that a malfunctioning canonical pathway will lead to an aberrant cellular response also through the non-canonical pathway.

Clinical significance

Overview of signal transduction pathways involved in apoptosis.

NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis. Defects in NF-κB results in increased susceptibility to apoptosis leading to increased cell death. This is because NF-κB regulates anti-apoptotic genes especially the TRAF1 and TRAF2 and thereby checks the activities of the caspase family of enzymes which are central to most apoptotic processes.[28]

In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IκB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.[29]

Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, gastritis, asthma, among others. Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. There is a controversial US patent (US patent 6,410,516)[30] that applies to the discovery and use of agents that can block NF-κB for therapeutic purposes. This patent is involved in several lawsuits, including Ariad v. Lilly. Recent work by Karin,[31] Ben-Neriah[32] and others has highlighted the importance of the connection between NF-κB, inflammation, and cancer, and underscored the value of therapies that regulate the activity of NF-κB.[33]

As a drug target

Aberrant activation of NF-κB is frequently observed in many cancers. Furthermore suppression of NF-κB limits the proliferation of cancer cells. In addition, NF-κB is a key player in the inflammatory response. Hence methods of inhibiting NF-κB signaling has potential therapeutic application in cancer and inflammatory diseases.[34][35]

The discovery that activation of NF-κB nuclear translocation can be separated from the elevation of oxidant stress[36] gives an important hint to the development of strategies for NF-κB inhibition.

A new drug called denosumab acts to raise bone mineral density and reduce fracture rates in many patient sub-groups by inhibiting RANKL which in turn through its receptor RANK inhibits NF-κB.[37]

Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade.[38]

Signaling in immunity

NF-kB is a major transcription factor that regulates genes responsible for both the innate and adaptive immune response. Upon activation of either the T- or B-cell receptor, NF-kB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, an adaptor molecule, ZAP70 is recruited via its SH2 domain to the cytoplasmic side of the receptor. ZAP70 helps recruit both LCK and PLC-γ, which causes activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-kB is able to enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.[39]

Conserved in evolution

NF-kB is found in a number of simple animals as well. These include cnidarians (such as sea anemones), porifera (sponges), and insects (such as moths, mosquitoes, and fruitflies). The sequencing of the genomes of the mosquitoes A. aegypti and A. gambiae, and the fruitfly D. melanogaster has allowed comparative genetic and evolutionary studies on NF-kB. In those insect species, activation of NF-kB is triggered by the Toll pathway (which evolved independently in insects and mammals) and by the Imd pathway.[40]

NF-κB in neurons

Though NF-κB is nearly ubiquitous in distribution, its role in neurons of the central nervous system is controversial. Several studies have claimed that the transcription factor is either constitutively active in neurons or activated by excitatory amino acid neurotransmitters or both. However, most of the suggestive data are imprecise, either depending on assays of whole-tissue homogenates (which include other cell types) or reporting only nuclear translocation without a measure of gene transactivation. Studies done with highly purified neurons (i.e., <1% contamination by other cell types) show no activation of NF-κB in response to previously reported agonists such as glutamate[41].

There is a rational argument to be made for restricting this transcription factor in neurons: NF-κB activity can result in expression of class I major histocompatibility complex (MHC I), targeting the cell for removal by cytotoxic T-cells. For the finite population of post-mitotic neurons, this would be maladaptive. Protection of neurons from T-cell-mediated killing via suppression of NF-κB, and thus MHC I, may be one factor in making neurons permissive hosts for viruses.

See also

References

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