Endocrinology 8th December 2016 The NF-Kb Pathway Expansion in the ligands and receptors is associated with the cell types and the specific pathways they want to activate Receptors that Use NF-kappa B - where it is absolutely classical · TNFR-1 (Tumour Necrosis Factor Receptor-1) · IL-1R (Interleukin-1 Receptor) · TLRs (Toll-like receptors) TLRs bind PAMPs-pathogen associated molecular patterns such as LPS (LPS binds to an adaptor that binds to TLR4) All three receptor families signal via adaptors, which bind directly to their cytoplasmic domains (don't have intrinsic enzymatic activity, instead they use adaptors to signal the response). All three activate NF-KB (nuclear factor kappa B) to up regulate the expression of pro-inflammatory genes. Only some of the receptors activate a death pathway (TNFR, FAS, TRAIL). TUMOUR NECROSIS FACTOR (TNF) RECEPTOR FAMILY TNF is an important cytokine in promoting inflammation. Anti-TNF therapy is effective in treating rheumatoid arthritis - bring down TNF can Cys-rich repeat bring down all the other cytokines involved in arthritis Bind to TNF and prevent it from binding to its receptor Bunch of cysteine repeats Death domain in the intracellular region I Death Domain: 80 a.a. (not all members contain death domains) TNFa Receptor Signaling (TNFR-1) Stoichiometry: 3 ligands: 3 receptors TNF is a trimer Driving apoptosis and survival: survival signals turned on quicker, and deactivates apoptosis - if the survival pathway is blocked, then the cell will die. Apoptosis Survival (NF-KB)
Endocrinology 8th December 2016 TRADD The Adaptor Protein TRADD Is Recruited Following Ligand Binding to TNFR- 1 TNF binding trimerizes the TNFR, allowing it to bind to the adaptor TRADD TNF Stoichiometry: 3 Ligands: 3 receptor chains: 3 adaptors (TRADD) TNF trimer trimerises the receptor Death domains are Homomeric; binds to other death domains TNFRI TRADD (TNF-receptor associated death domain) has a death domain (DD) and a death effector domain (DED) - binds to the death domain - gets the death domains in the right orientation of them to send down the signals 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 called 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 - activate pro-caspase 8 TRADD, FADD and Pro-Caspase 8 DD DED 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 FADD RIP TRAF2 TRADD pro-caspase 8 TRADD NFKB, Jun Figure 6-32 Immunobiology, 7ed. (@ Garland Sc Bringing the pro-caspases together, and close enough so they can cleave each other and then activate the caspase cascade Caspase 8 The high concentration of pro-caspase-8 at the receptor allows pro-caspase 8 to activate itself by cleaving itself. Caspase 8 is an initiator caspase, it activates other effector caspases. CASPASE ACTIVATION Need to cut out