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  • Created by: jo bill
  • Created on: 21-12-14 11:31

Receptors which use NF-kappa B

  • TNFR-1 (tumour necrosis factor receptor-1)
  • IL-1R (interleukin-1 receptor)
  • TLRs (toll-like receptors

-TLRs bind PAMPs -pathogen associated molecular patterns

-all three receptor families signal via adaptors which bind directly to their cytoplasmic domains

-all three activate NF-kB to upregulate the expression of pro-inflammatory genes

-only some of the receptors activate a death pathway

TUMOUR NECROSIS FACTOR (TNF) RECEPTOR FAMILY

  • TNF is an important cytokine in promoting inflammation
  • ANti-TNF therapy is effective in rheumatoid arthritis

TRADD

  • the adaptor protein TRADD is recruited following ligand binding to TNFR-1
  • stoichiometry : 3 ligands, 3 receptor chains, 3 adaptors
  • TRADD has a death domain(DD) and a death effector domain (DED)
  • the death domain of TRADD binds to the death domain of TNFR-1
  • TRADD is required for BOTH cell death and NF-kB pathways

FADD

  • to activate the death pathway, TRADD recruits another adaptor - FADD
  • FADD also has a death domain and a death effector domain
  • the death effector domain of FADD recruits pro-caspase-8 by binding to the death effector domain of pro-caspase-8

caspase - 8

  • the high concentration of procaspase-8 at the receptor allows pro-caspase 8 to activate itself by cleaving itself
  • caspase 8 is an iniator caspase, it activates other effector caspases
  • CASPASE 8 ACTIVATES EFFECTOR CASPASES 3,6,7
  1. activate more caspases 
  2. cell shrinkage and membrane blebbing
  3. DNA fragmentation

TRADD, FADD and pro-caspase 8

  • TNF binding trimerizes the TNFR, allowing it to bind to the adaptor TRADD
  • in a pathway that induces death, TRADD can recruit FADD, resulting in caspase 8 activation
  • in a pathway that induces new gene transcription, TRADD recruits RIP and TRAF2

summary of the death pathway

  • death receptors such as FAS and TNFR-1 signal death by:
  • recruiting adaptor protains that in turn recruit iniator…

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