NF-κB Signaling

The Nuclear factor kappa B (NF-κB) transcription factors are key regulators of gene expression culminating in response to stress and the development of innate and acquired immunity. A multitude of extracellular stimuli can lead to NF-κ B activation. These include cytokines, infections, oxidative and DNA-damaging agents, UV light, and osmotic shock. NF-κ B transcription factors bind to DNA as hetero- or homodimers that are derived from five known subunits (RELA/p65, c-REL, RELB, p50, and p52).The RELA/p65 and p50 subunits are ubiquitously expressed, while the p52, c-REL, and RELB subunits are found in more specific cell types. In situations where there is no stress to a cell, cytoplasmic p50/p65 heterodimers, c-REL homodimers, and RELB are bound to Iκ Bs (inhibitors of NF-κ B), thereby sequestering them in the cytoplasm. Activators of NF-κ B mediate the site-specific phosphorylation of serine on Iκ B, thereby marking Iκ B for ubiquitination and subsequent proteasomal destruction. NF-κ B is then free to translocate to the nucleus and bind DNA leading to the activation of a host of inflammatory response target genes. Several factors can directly or indirectly activate NF-κ B mediated transcription.Iκ B is among the genes upregulated by NF-κ B. When expressed in the nucleus, Iκ B not only inhibits NF-κ B mediated transcription, but also transports NF-κ B back to the cytoplasm. This function of Iκ B is insured by a nuclear export sequence located in its C-terminal domain. Thus Iκ B is part of an important autoregulatory loop. In contrast to RELA/p65, c-REL, and RELB, the NF-κ B p50 and p52 subunits do not bind to Iκ B - instead they are derived from p105 and p100 precursor proteins by the IKK mediated removal of carboxyl-terminal Iκ B-like domains.Phosphorylation of Iκ B , the key event in NF-κ B activation, is mediated by a high molecular weight complex consisting of two Iκ B kinases (IKKα and IKKβ) and a noncatalytic regulatory subunit (IKKγ). The IKKs themselves are activated by signals from a diverse group of receptors that include cytokine receptors, T cell receptors and growth factor receptors. For e.g. the B-cell leukemia/lymphoma 10 protein (BCL10) and the paracaspase Mucosa associated lymphoid tissue lymphoma translocation1 protein (MALT1) are essential for the activation of IKK and in NF-κ B response to T cell receptor (TCR) stimulation. The activation of IKK by the MAPK kinase kinase (MAPKKK) MEKK3 is pivotal in TNF-induced NF-κ B activation. Growth factor dependent activation of NF-κ B involves the phosphorylation of IKK by the MAPKKK COT and its upstream enzyme AKT. Thus IKK serves as an important link between extracellular signals and NF-κ B response, via the phosphorylation and degradation of Iκ B.This pathway highlights the important components of the NF-κ B signaling pathway.