All tags NF-kB p65 and the NF-κB inflammatory pathway

p65 and the NF-κB inflammatory pathway

By David Bruce, PhD

p65, also known as RelA, is one of the five components that form the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcription factor family.

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 cells (Napetschnig and Wu, 2013; Bassères and Baldwin, 2006).

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 repeats (Napetschnig and Wu, 2013; Bassères and Baldwin, 2006).

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 cancer (Courtois et al., 2006; Gutierrez and Davies, 2011).

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 bind 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 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 located to 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 are 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-acetylglucosylation, ubiquitylation, nitrosylation, acetylation, prolyl isomerization, methylation as well as phosphorylation. The best studied family member is p65 (reviewed by Napetschnig and Wu, 2013; Gilmore, 2006).

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 replication (Hiscott et al.,

References

  • Bassères DS, Baldwin AS (2006) Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006 Oct 30;25(51):6817-30.
  • Courtois G, Gilmore TD (2006) Mutations in the NF-kappaB signaling pathway: implications for human disease.Oncogene. 2006 Oct 30;25(51):6831-43.
  • Gilmore TD (2006). Introduction to NF-κB: players, pathways, perspectives.Oncogene 25 (51): 6680–4
  • Gutierrez H, Davies AM (2011) Regulation of neural process growth, elaboration and structural plasticity by NF-κB.Trends Neurosci. 2011 Jun;34(6):316-25.
  • Hiscott J, Kwon H, Génin P (2001) Hostile takeovers: viral appropriation of the NF-kappaB pathway.J Clin Invest. 2001 Jan;107(2):143-51
  • Napetschnig J, Wu H (2013) Molecular basis of NF-κB signaling. Annu Rev Biophys. 2013;42:443-68.
  • Surjit M, Varshney B, and Lal S (2012) 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. 2012; 13: 7.