4.
Caspases are required for Rpr-, Grim-, Hid-, and SkI-induced
apoptosisSeven caspases have been identified in Drosophila. Dredd/Dcp-2 (Inohara et al., 1997;
Chen et al., 1998), Dronc/Nc (Dorstyn et al., 1999b), and Strica/Dream (Doumanis
et al., 2001) appear to be initiator caspases, as they contain long N-terminal
prodomains. Dronc has a caspase recruitment or CARD domain, while the Dredd
prodomain shows some similarity to the death effector domain (DED). The long
serine/threonine-rich prodomain of Strica bears no obvious homology to other
caspase prodomains. The caspases Dcp-1 (Song et al., 1997), drICE (Fraser and Evan,
1997), Decay (Dorstyn et al., 1999b), and Damm (Harvey et al., 2001) have the
shorter prodomains consistent with executioner caspases.
Dronc is expressed in many cells of the developing embryo (Dorstyn et al., 1999b).
Genetic reduction of Dronc indicates that Dronc mediates apoptosis initiated by Rpr
and Hid (Quinn et al., 2000). In the embryo, reduction of Dronc by the RNA
interference technique (reviewed in Sharp, 1999) suggests that Dronc is required for
most developmental apoptosis. Interestingly, Dronc expression is induced by the
steroid hormone ecdysone, which is a key regulator of apoptosis during
metamorphosis (Dorstyn et al., 1999b). No mutant alleles of Dronc have been
isolated, so the role of Dronc in ecdysone-induced death has not yet been assessed.
Ectopically expressed Dronc can induce cell death in yeast cultured cells and cells
in the developing Drosophila eye (Dorstyn et al., 1999b; Hawkins et al., 2000; Meier
et al., 2000). Dronc has been shown to have an interesting substrate specificity: it is
autoprocessed after a glutamate, but cleaves drICE after a more typical aspartate
(Hawkins et al., 2000; Meier et al., 2000). Dronc activation appears to require the
activity of the Drosophila Apaf-1 homolog, Ark (Quinn et al., 2000; Dorstyn et al.,
2002).
Like Dronc, the long prodomain containing caspase Dredd physically interacts
with Ark (Rodriguez et al., 1999). Although mutations in Dredd suppress apoptosis
induced by Rpr and Grim, apoptosis induced by Hid is not effectively suppressed
(Chen et al., 1998). This supports the idea that different caspases may function
downstream of the apoptotic inducers. This specificity also appears to extend to the
executioner caspases, as described below.
The pattern of Dredd expression is particularly interesting (Chen et al., 1998).
Dredd transcripts appear to accumulate in cells that are fated to die in the embryo.
Surprisingly, this accumulation is dependent on the expression of the apoptotic
inducers Rpr, Grim, and Hid, as embryos homozygous for a deletion of these genes
do not show wild-type Dredd expression. The mechanism by which this regulation
of Dredd expression occurs is not yet known.
A role for Dredd outside apoptosis has also been uncovered. The innate immune
response in flies is mediated in part by NFκB-dependent transcription of antibacterial
and antifungal peptides (Hoffmann and Reichhart, 1997). Mutations in Dredd
suppress the antibacterial response (Elrod-Erickson et al., 2000; Leulier et al., 2000).
APOPTOSIS IN DROSOPHILA 189