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NF-Κb

What is NF-κB?

NF-κB is short for nuclear factor kappa-light-chain-enhancer of activated B cells. It is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens^[1,2]. NF-κB plays a key role in regulating the immune response to infection. 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^[3].

Fig.1 NF-κB is a central regulator in stress response^[4]

Members

NF-κB contains 5 family members: p65/relA, relB, c-rel, p50/NF-κB1, and p52/NF-κB2, and they could be divided into 2 classes.

Fig.2 Schematic diagram of NF-κB protein structure^[5]

There are two structural classes of NF-κB proteins: class ǀ and class ǁ. Both classes of proteins contain an 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 ǀ proteins contains a number of ankyrin repeats and has transrepression activity. In contrast, the C-terminus of class ǁ proteins has a transactivation function.

Immunity

NF-κB 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-κB becomes activated through distinct signaling components. Upon ligation of the T-cell receptor, protein kinase Lck is recruited and phosphorylates the ITAMs of the CD3 cytoplasmic tail. ZAP70 is then recruited to the phosphorylated ITAMs and helps recruit LAT and PLC-γ, which causes the activation of PKC. Through a cascade of phosphorylation events, the kinase complex is activated and NF-κB can enter the nucleus to upregulate genes involved in T-cell development, maturation, and proliferation.

Reference

[1] Gilmore TD (October 2006). Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 25 (51): 6680-6684.

[2] Tian B, Brasier AR (2003). Identification of a nuclear factor kappa B-dependent gene network. Recent Progress in Hormone Research. 58: 95-130.

[3] Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (October 2003). "NF-kappa B functions in synaptic signaling and behavior". Nature Neuroscience. 6 (10): 1072-1078.

[4] Jeremy S. Tilstra1, Cheryl L. Clauson1. NF-κB in Aging and Disease. Aging and Disease. 2 (6): 449-465.

[5] Biancalana M, Natan E, Lenardo MJ, (September 2021). NF-κB Rel subunit exchange on a physiological timescale. Protein Science. 30 (9): 1818-1832.

[6] Livolsi A, Busuttil V, Imbert V, Abraham RT, Peyron JF (March 2001). Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases. European Journal of Biochemistry. 268 (5): 1508–1515.

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