NFkappaB

• Role in the cell

  • Play a role in acute response to a pathogen, regulating innate and adaptive responses, pro-inflammatory cytokines, apoptosis/cell survival
• Alternative pathway activation

  NIK activation -> IKKa homodimer activation -> phosphorylation of p100 + ubiquitination -> p52 generation and formation of dimer with RelB -> translocation into nucleus to induce gene expression
• Viral infection

  PAMPs (e.g., viral nucleic acid) recognised by PRRs -> activation of NFkappaB signalling -> upregulation of pro-inflammatory cytokines, host immune responses, and factors positively regulating the cell cycle
• Viruses


  Manipulate NFkappaB to increase virulence and viral transcription/replication, e.g., HIV-1 includes NFkappaB binding sites in viral genome
• Viruses

  Can take advantage of NFkappaB signalling for more viral replication/spread and to evade immune responses, although it mostly results in an antiviral effect
• Canonical pathway sensor

  Range of PRRs (pattern recognition receptors) incl. TLRs, RLRs, Nod-like receptors -> IkB (IKK) complex
• Alternative pathway sensor

  NF-KB inducing kinase (NIK) -> IKKalpha homodimers activated
• NFkappaB signalling

  Can contribute to more pathology resulting from inflammation, e.g., inducing COX-2 enzyme
• Family of dimeric transcription factors

  • RelA, RelB, c-Rel, p50, p52
• NFkappaB signalling activation

  • Activated by multiple pathways, e.g., canonical pathway (triggered by TNF-a, viral nucleic acid) or alternative pathway (triggered by TNFSF ligands like CD40L)
• Canonical pathway activation trigger

  Pro-inflammatory cytokines (e.g., TNF-a) or viral dsRNA
• Alternative pathway activation trigger

  TNF-ligands (e.g., LT-ßR, CD40L, RANK)
• HIV-1


  Includes NFkappaB binding sites in viral genome, downregulates NFkappaB-interacting long non-coding RNA (NKILA), encoded proteins suppress immune response and inhibit apoptosis of infected cells
• Canonical pathway activation

  IKK complex formation -> phosphorylation of IKBa -> ubiquitin-dependent degradation of IKBa -> release of NFkappaB into nucleus -> induction of gene expression
• Contribution to antiviral immunity

  • Upregulation of antiviral interferons and pro-inflammatory cytokines, facilitation of host immune responses, apoptosis of infected cells