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P65 and the Nf-κB inflammatory pathway

Read about p65 and the NF-κB inflammatory signaling pathway in this review by David Bruce, PhD.
Last edited Tue 15 Dec 2020

The remaining members include RelB, c-Rel, and cleaved proteins NF-κB1 (p50) and NF-κB2 (p52). p50 and p65 form the most common heterodimer in the NF-κB signaling pathway, present in most cell types. In contrast, other members, for example, c-Rel, are predominantly found only in hematopoietic cells1,2.

p65, RelB, and c-Rel are characterized by a Rel homology domain located in the N-terminal, which is combined with a transactivating domain in the C-terminal. In contrast, NF-κB1 and NF-κB2 are processed from large precursors (p105 and p100, respectively) into p50 and p52 subunits. This is a ubiquitin-mediated process, involving selective degradation from the C-terminal to remove ankyrin repeats1,2.

As part of the NF-κB signaling pathway, p65 is typically involved in the body’s inflammatory response. This pathway can be induced by stressful stimuli, including free radicals, ultraviolet irradiation (UV),  tumor necrosis factor α (TNFα), interleukin 1-beta (IL-1β), pathogen-associated molecular patterns (PAMPs), or bacterial lipopolysaccharides (LPS). NF-κB has been implicated in memory and synaptic plasticity while aberrant protein levels have been linked to cancer3,4.

NF-κB pathway following inflammatory signaling

In unstimulated cells, NF-κB subunits are restricted to the cytoplasm due to the inhibitory effects of the inhibitor of κB (IκB) family. IκBα or IκBβ selectively binds to the p50/p65 heterodimer and masks their nuclear localization signal (NLS), preventing their nuclear translocation.

Stressful stimuli induce NF-κB signaling through several cell membrane-bound receptors that converge on the activation of the IκB kinase (IKK) complex. The activated IKK complex phosphorylates IκBα, priming it for subsequent ubiquitylation and proteasome-mediated degradation. Disassociation of IκBα induces NF-κB heterodimers to locate in the nucleus and bind to specific gene promoters to modulate the expression of pro- and anti-inflammatory proteins. As a negative feedback loop, the expression of IκBα and  IκBβ is up-regulated by the NF-κB heterodimers, in order to terminate the signaling pathway.

NF-κB subunits have been reported to be extensively modified, including O-linked N-acetyl glycosylation, ubiquitylation, nitrosylation, acetylation, prolyl isomerization, methylation as well as phosphorylation. The best-studied family member is p651,5.

NF-κB signaling plays a crucial role to fight infections, however, some pathogens have developed ways to alter NF-κB activity to their advantage. For example, the Human immunodeficiency virus (HIV) contains binding sites within its genome for NF-κB subunits, which drive viral gene expression as well as boosting its replication6.

View tools for NF-κB research.



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Surjit M.,, Varshney B.,, Lal S. The ORF2 glycoprotein of hepatitis E virus inhibits cellular NF-κB activity by blocking ubiquitination mediated proteasomal degradation of IκBα in human hepatoma cells BMC Biochem 13 ,7 (2012)