TRAIL & its Receptors

Figure 1. Bax moves from the cytosol to the mitochondria before cell shrinkage and nuclear fragmentation. a. Induction of apoptosis with staurosporin or gamma-irradiation; b. movement of bax from the cytosol to the membranes; c. cell shrinkage; d. nuclear fragmentation.

TRAIL, TNF-related apoptosis-inducing ligand, also known as apo-2 ligand, is a member of the TNF family of proteins and is a type II membrane protein.1, 2 Soluble active TRAIL is generated by deletion of the transmembrane and intracellular domains. The active soluble TRAIL is homo-trimeric.2 TRAIL induces apoptosis when it binds to the cell surface receptors TRAIL R-1 (DR-4)3 and TRAIL R-2 (DR-5).4-9 By analogy with TNF-alpha binding to the 55-kDa TNF receptor, with known crystal structure,10 TRAIL trimer is likely bound by three TRAIL receptor polypeptides. In this model each receptor polypeptide is positioned in the groove formed by two adjacent ligand polypeptides, with receptor contacts with the two adjacent TRAIL polypeptides.

Receptor oligomerization (likely to be trimerization) is a common theme among many of the apoptosis-inducing receptors (e.g. TNF R-1, TRAIL R-1, TRAIL R-2, and FAS).11-14 Trimerization appears to be required to bring intracellular death domains into close proximity. Aggregation of the death domains induces the assembly of intracellular proteins required to initiate apoptosis. FAS and TNF R-1 recruit a protein named FADD; induction of apoptosis depends on this protein. Studies with a dominant negative mutant form of FADD3 or with embryonic cells from FADD knockout mice15 indicate, however, that FADD is not required for induction of apoptosis by TRAIL. Thus, at least one of the TRAIL receptors induces apoptosis by a FADD-independent pathway. TRAIL binding leads to the activation of caspase 8 and TRAIL-induced apoptosis can be blocked by inhibitors of caspase 8 (FLICE).3 The molecular connections linking TRAIL R-1 and TRAIL R-2 to caspase 8 activation are unknown.

TRAIL R-3 and TRAIL R-4 are also known as decoy receptors-1 and -2. TRAIL R-3 is tethered to the plasma membrane through a glycophosphatidyl anchor,4, 5, 16 while TRAIL R-4 has a truncated intracellular domain.17, 18 Neither receptor can induce apoptosis, but each inhibits TRAIL-induced apoptosis mediated by TRAIL R-1 and/or TRAIL R-2 when coexpressed. Normal cells appear to express TRAIL R-3 and/or TRAIL R-4 in conjunction with TRAIL R-1 and/or TRAIL R-2. Expression of the decoy receptors appears to protect normal cells from TRAIL-induced apoptosis.4, 5 Many tumor cell lines do not express the decoy receptors and are therefore sensitive to TRAIL if they express TRAIL R-1 and/or TRAIL R-2.


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