Abstract
Death receptors are a subfamily of the tumor necrosis factor (TNF) receptor subfamily. They are characterized by a death domain (DD) motif within their intracellular domain, which is required for the induction of apoptosis. Fas-associated death domain protein (FADD) is reported to be the universal adaptor used by death receptors to recruit and activate the initiator caspase-8. CD95, TNF-related apoptosis-inducing ligand (TRAIL-R1), and TRAIL-R2 bind FADD directly, whereas recruitment to TNF-R1 is indirect through another adaptor TNF receptor-associated death domain protein (TRADD). TRADD also binds two other adaptors receptor-interacting protein (RIP) and TNF-receptor-associated factor 2 (TRAF2), which are required for TNF-induced NF-kappaB and c-Jun N-terminal kinase activation, respectively. Analysis of the native TNF signaling complex revealed the recruitment of RIP, TRADD, and TRAF2 but not FADD or caspase-8. TNF failed to induce apoptosis in FADD- and caspase-8-deficient Jurkat cells, indicating that these apoptotic mediators were required for TNF-induced apoptosis. In an in vitro binding assay, the intracellular domain of TNF-R1 bound TRADD, RIP, and TRAF2 but did not bind FADD or caspase-8. Under the same conditions, the intracellular domain of both CD95 and TRAIL-R2 bound both FADD and caspase-8. Taken together these results suggest that apoptosis signaling by TNF is distinct from that induced by CD95 and TRAIL. Although caspase-8 and FADD are obligatory for TNF-mediated apoptosis, they are not recruited to a TNF-induced membrane-bound receptor signaling complex as occurs during CD95 or TRAIL signaling, but instead must be activated elsewhere within the cell.
Highlights
Death receptors such as CD95 (Fas/Apo1), tumor necrosis factor (TNF)1 receptor-1 (TNF-R1) and the TNF-related apo
TNF-induced signaling is believed to diverge at this point; TNF-receptor-associated factor 2 (TRAF2)/receptor-interacting protein (RIP) recruitment leads to activation of downstream kinases in the NF-B and c-Jun N-terminal kinase (JNK) pathways, whereas Fas-associated death domain protein (FADD) recruitment leads to apoptosis [20]
TNF receptor-associated death domain protein (TRADD), RIP, and TRAF2, but Not FADD or Caspase-8, Are Recruited to the TNF-induced Signaling Complex—Treatment of Jurkat T cells with biotinylated TNF (bTNF), which retained the properties of unlabelled TNF-␣, led to the rapid recruitment of TRADD, RIP, and TRAF2 to the precipitated complexes (Fig. 1A)
Summary
Death receptors such as CD95 (Fas/Apo1), tumor necrosis factor (TNF)1 receptor-1 (TNF-R1) and the TNF-related apo-. TRADD binds two other adaptors receptor-interacting protein (RIP) and TNF-receptor-associated factor 2 (TRAF2), which are required for TNF-induced NF-B and c-Jun N-terminal kinase activation, respectively.
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