endo

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…