Overexpression of an upstream mediator of this response, Imd, results in increased
Rpr expression and apoptosis (Georgel et al., 2001). It will be interesting to test
whether Rpr itself might play a role in innate immunity.
The Strica prodomain is high in serine and threonine residues, and shares no
obvious homology to other caspase prodomains (Doumanis et al., 2001). It is widely
expressed during development, and accumulates in some tissues fated to undergo
apoptosis. Although its structure suggests that it is an apical caspase, no role has yet
been defined for Strica in developmental apoptosis. One unique feature of Strica is
that it can bind to both DIAP1 and DIAP2, while Dronc, Dcp-1, and drICE have
only been found to bind to DIAP1.
Among the putative effector caspases, Dcp-1, drICE, and Decay most resemble
mammalian caspase-3 (Kumar and Doumanis, 2000). Mutants in Dcp-1 have been
characterized (Song et al., 1997; McCall and Steller, 1998). Although these mutants
show no detectable defects in embryonic apoptosis, Dcp-1 plays an important role
in oogenesis. If the female germ line lacks Dcp-1, the transfer of nurse-cell contents
to the developing egg is inhibited. This nurse-cell ‘dumping’ appears to be a modified
form of apoptosis. Dcp-1-mutant animals also have other defects that may indicate
a role for this caspase in other developmental events. Activation of Dcp-1 is facilitated
by Rpr and Grim, but not Hid, expression, suggesting that this caspase may act
selectively downstream of Rpr and Grim (Song et al., 2000).
Specific roles for drICE, Decay, and Damm have not yet been identified. However,
depletion of drICE from extracts of Drosophila S2 tissue-culture cells inhibits some
apoptotic activity in these extracts (Fraser et al., 1997). Expression of catalytically
inactive, and presumably dominant negative, Damm can block apoptosis induced by
ectopically expressed Hid, but not Rpr, again suggesting specificity in the downstream
caspases (Harvey et al., 2001).
5.
Modifiers of caspase activation: the mitochondrial pathwayOne provocative difference between the C.elegans and mammalian apoptotic
pathways is the function of the ced-4/Apaf-1 caspase activator. In worms, the
apoptosome contains the caspase ced-3, the adapter ced-4, and the bcl-2-like protein
ced-9, with ced-9 inhibiting ced-4 activation of ced-3 (reviewed in Chapter 9). This
inhibition is relieved by the proapoptotic activity of the BH3 protein, egl-1. The
mammalian apoptosome also consists of a caspase (usually caspase-9), and an adapter
(Apaf-1). However, Apaf-1-mediated activation is inhibited by the c-terminal WD
repeats of Apaf-1. Binding of cytochrome c to this domain relieves this inhibition
(reviewed in Chapter 7). Bcl-2 family members seem to act upstream, regulating the
release of mitochondrial proteins, including cytochrome c.
Drosophila appears to share characteristics with both of these systems. The Apaf-1/
ced-4 homolog, Ark, is clearly important for the full response to Rpr, Grim, and Hid
activation, and interacts with at least two apical caspases, Dronc and Dredd (Kanuka
et al., 1999; Rodriguez et al., 1999; Zhou et al., 1999). One form of Ark contains a
190 GENETICS OF APOPTOSIS