NF-kappaB signaling system

The NF-kappaB signaling pathway (NF-kappaB/NF-κB stands for: Nuclear factor "kappa-light-chain-enhancer" of activated B cells) is a cellular signaling pathway that regulates the transcription of genes involved in inflammation, immune response, cell proliferation, survival and apoptosis. The NF-kappaB signaling pathway controls the cellular response to stress, inflammation and infection. In the resting state, NF-κB is inhibited by IκB. The NF-kappaB signaling system (defined by the interactions between NF-kappaB dimers, IkappaB regulators and IKK complexes) responds to a range of stimuli. Upon ligand-receptor interaction, different cellular outcomes are initiated depending on the specific signal received (Hayden MS et al. 2004).

Inflammation-promoting cytokines such as IFN-gamma and TNF-alpha activate the IKK complex, which phosphorylates IκB and marks it for proteasomal degradation. As a result, NF-kappaB is released and can migrate into the cell nucleus after phosphorylation. In the nucleus, NF-kappaB acts alone or together with other transcription factors such as AP-1 and STAT to induce the expression of target genes. In addition to activation by cytokines, this signaling pathway can be activated by cellular stress factors such as UV light, toxic chemicals and ischemia. JNK (also known as stress-activated protein kinase) also activates NF-kappaB and enables the expression of target genes. Similarly, JAK, which is associated with cytokine receptors, phosphorylates STAT and enhances NF-kappaB-STAT-mediated gene expression.

Important components:

• NF-κB proteins: Transcription factors, mostly as dimers (e.g. p65/RelA, p50, c-Rel, RelB, p52)
• Inhibitors (IκB): Cytoplasmic proteins that bind NF-kappaB in the resting state and keep it inactive (e.g. I-kappaB-alpha)
• IKK complex (I-kappaB kinase complex): Consists of IKK-alpha, IKK-beta and the regulatory protein NEMO (IKK-gamma) - this activates the signaling pathway by phosphorylating IKappaB.
• Signaling pathway activation (classical/canonical pathway):
• Stimuli (e.g. TNF-alpha, interleukin-1beta, bacterial LPS) activate receptors (e.g. TNF receptors and TLRs). The IKK complex is activated.
• I-kappaB alpha is phosphorylated, ubiquitinated and degraded.
• NF-kappaB dimers (e.g. p65/p50) are released and translocate into the cell nucleus. There they bind to specific DNA sequences and activate target genes (e.g. interleukin-6, TNF-alpha, COX-2, Bcl-2).

Non-canonical pathway:

This signaling pathway is activated by certain stimuli (e.g. BAFF, CD40L)

It leads to the formation of p52/RelB dimers

It is important for adaptive immune response and development of lymphoid organs