4.2
Inhibition of DD signaling by silencer of death domains (SODD)The DDs of death receptors (TNF-R1, CD95, DR3, DR4, and DR5) can self-
associate and bind other DD-containing proteins. Overexpression of DD receptors
may lead to ligand-independent receptor aggregation and cell death. However, cells
are protected from such spontaneous ligand-independent signaling by death receptors
via expression of a ~60-kDa protein termed silencer of death domains (SODD) (Jiang
et al., 1999). SODD associates with the DDs of TNF-R1 and inhibits the intrinsic
self-aggregation of the DD (Jiang et al., 1999). This inhibition is lost by triggering
the release of SODD from the DD in response to cross-linkage of TNF-R1 with
TNF-α. This allows ligand-dependent recruitment of adapter proteins to form an
active signaling complex. However, the duration of TNF signaling is controlled by
the rapid dissociation of signaling proteins from TNF-R1 and reformation of the
TNF-R1-SODD complex (Jiang et al., 1999). While SODD interacts with TNF-R1
and DR3, other SODD-related proteins may play a similar role in preventing ligand-
independent signaling by CD95, DR4, or DR5.
4.3
Regulation of caspase-8 by FLICE-inhibitory proteins (FLIPs)The recruitment and activation of caspases by death receptor engagement can be
inhibited by FLICE-inhibitory protein (FLIP; also called I-FLICE, CASH, CLARP,
MRIT, or usurpin) (Bertin et al., 1997; Goltsev et al., 1997; Han et al., 1997; Hu et
al., 1997; Inohara et al., 1997; Irmler et al., 1997; Srinivasula et al., 1997; Thome et
al., 1997; Rasper et al., 1998; Chai, J. et al., 2001). FLIP contains death-effector
domains (DEDs) that bind to the DED of FADD and the prodomains of
procaspases-8 and -10, thereby inhibiting their recruitment to the CD95-FADD—
or TNFR1-induced activation complex (Goltsev et al., 1997; Han et al., 1997;
Goltsev et al., 1997; Han et al., 1997; Irmler et al., 1997; Srinivasula et al., 1997).
Enforced expression of v-FLIP (found in γ-herpes and pox viruses) inhibits apoptosis
induced by CD95, TNFR1, DR3, and DR4/TRAIL-R1 (Thome et al., 1997). The
equine herpes II virus E8 protein and molluscum contagiosum MC159 and MC160
also contain DEDs homologs to those of procaspase-8, and inhibit its recruitment to
the death receptor signaling complex (Bertin et al., 1997).
Multiple splice variants of the human homologs of FLIP have been identified. The
longer, more abundant form, FLIPL, has two DEDs and a caspase-like C-terminal
domain, but lacks the catalytic cysteine and histidine residues that contribute to
substrate binding. The shorter splice variant, FLIPS, comprises only the two DEDs.
The effects of cellular FLIPs appear to vary depending on the cellular context.
Enforced expression of FLIP (the long splice variant) has an apparently paradoxical
pro-apoptotic effect, possibly mediated by the aggregation of procaspase-8. However,
experiments with c-FLIP-deficient mice support an antiapoptotic role of c-FLIP that
is analogous to its viral counterparts. Embryonic fibroblasts from c-FLIP-deficient
DEATH RECEPTORS IN APOPTOSIS 11