24.5:
NF-kB-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.
24.5:
NF-kB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB exists in the inactive state in the cytoplasm of the resting cells. The inhibitory protein, IκB, masks the nuclear localization signals of the NF-κB. On induction of cells by external stimuli – such as pathogens or reactive oxygen species – the IκB is tagged and subsequently degraded in the proteasome. The free NF-κB can then act as a transcriptional activator for its target genes in the cell nucleus. The activation of these genes then allows the cell to mount an appropriate physiological response.
NF-κB Function and Associated Diseases
Besides acting as a central mediator of immune responses in animals, studies have revealed several other roles of NF-κB. These include the regulation of cell proliferation and apoptosis, tumor formation, and multiple and diverse functions in the nervous system – such as learning and memory.
Additionally, the NF-κB signaling pathway also acts as a target for some viral as well as bacterial pathogens. Pathogens like HIV, HPV, and Yersinia pestis have developed strategies to exploit or interfere with the NF-κB signaling pathway to evade host defense mechanisms. Because of its diverse roles in animals, the NF-κB signaling pathway is an excellent therapeutic target.
Suggested Reading
- Sarkar F.H. et al. NF-κB Signaling Pathway and Its Therapeutic Implications in Human Diseases. International Reviews of Immunology, 27:293–319 (2008)