RESEARCH ARTICLE
Dual Philosophy in Death Receptor Signalling

ABSTRACT

Tumour necrosis factor (TNF) is the founding member of a cytokine family with important roles in both, physiology and pathological conditions. The two seemingly opposing cellular responses to stimulation by TNF itself are death and induction of pro-inflammatory signalling. TNF and other TNF superfamily (SF) members signal by crosslinking their cognate receptors. These form part of the TNF receptor SF (TNFRSF). Members of this family have between two and six characteristic cysteine-rich repeats in their extracellular domain. These repeats are crucial for receptor-ligand interaction. Members of the TNFRSF come in three flavours: as type I transmembrane proteins, attached to the plasma membrane by a glycosyl¬phosphatidyl¬inositol (GPI) anchor, or as secreted soluble proteins. The latter receptors act as decoys for their respective ligands. To date 30 members of the TNFRSF are known. Six of them form part of the subfamily of the death receptors. Death receptors are characterised by the presence of an intracellular death domain (DD). Amongst the death receptors there are again at least two subclasses, the ones which recruit the Fas-Associated Death Domain (FADD) and the ones that recruit the TNFR-Associated Death Domain (TRADD) protein. The primary function of FADD-recruiting receptors is to induce apoptosis whilst the primary function of the TRADD recruiters is to activate pro-inflammatory signalling (Fig. 1). However, from a second platform both systems are also capable of triggering the respective other signalling outcome

Fig. (1) The 6 human DD-containing receptors and their known ligands. The six human DD-containing receptors, TNF-R1 (p55/p60 TNF-R), CD95 (Fas, APO-1), death receptor 3 (DR3, TRAMP), TRAIL-R1 (DR4), TRAIL-R2 (DR5) and DR6 (TNFRSF21) are activated by their respective ligands: TNF, CD95L (FasL/APO-1L), TL1A, TRAIL (Apo2L), and a specific amino-terminal cleavage fragment of the β-amyloid precursor protein (APP), N-APP. They are transmembrane proteins which contain repeats of 2-4 cysteine-rich domains (CRDs) in the extracellular portion required for ligand binding and an intracellular death domain (ICD) capable of recruiting specific adaptors proteins. Whilst the primary signal output of the TRADD-recruiting ICDs of TNF-R1 and DR3 (shown in dark grey) is the activation of inflammatory signalling, the FADD-recruiting ICDs of CD95 and the TRAIL death receptors (shown in light grey) induce apoptosis as their primary signalling output.

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