14.4 : NF-κB-dependent Signaling Pathway

NF-κB proteins are transcription factors that are involved in many crucial cellular functions such as immune cell activation, cell adhesion, antimicrobial response, and cell cycle regulation.

In the resting state, the NF-κB exists as a heterodimer directly bound to an inhibitory protein called IκBɑ. IκBɑ suppresses the activity of NF-κB as a transcriptional activator.

The NF-κB-dependent signaling pathway is activated upon binding of an appropriate ligand to its corresponding cell-surface receptor on the target cell.

For example, the pathway can be triggered by binding of tumor necrosis factor-ɑ to the TNF receptor, binding of interleukin 1 to the IL1 receptor, or binding of pathogens to toll-like receptors.

This ligand-receptor binding results in the activation of a protein complex, IκB kinase,  consisting of three subunits, ɑ, β, and γ.

The activated kinase then phosphorylates the IkB protein leading to its ubiquitination.

The marked IκB protein then undergoes immediate degradation in the proteasome.

As a result, the NF-κB dimer is released from IκB and is free for its translocation to the nucleus where it can activate the expression of a number of target genes.

One of the target genes activated by NF-κB is the gene that encodes the IκBɑ protein. Upon its increased expression, IκBɑ assists in regulating the NF-κB-dependent Signaling Pathway via a negative feedback loop.

The NF-κB-dependent signaling pathway acts to control a broad range of biological processes, including innate and adaptive immunity and inflammatory stress responses.

Due to its pivotal role in immune as well as inflammatory responses in animals, dysregulation of NF-κB can lead to various types of cancers, as well as several inflammatory diseases, such as arthritis and asthma.