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Apoptosis

Grim, reaper and the sickle of death

In 1994, a fly strain was discovered that is essentially defective in developmental cell death. This strain bears a homozygous genomic deletion (called H99). Three genes — reaper , hid and grim — were subsequently identified that map to this deletion, and regulate programmed cell death by similar mechanisms. Now, reporting in Current Biology, three laboratories have identified Sickle, a fourth homologue in Drosophila melanogaster, that seems to acts in parallel with Reaper and Grim.

Reaper, Hid and Grim not only map close together, but they are also structurally related. The homology is limited to the amino-terminal 10–15 amino acids, and to a 30-amino-acid region called the 'Trp block'. The three proteins also function by a similar mechanism — they regulate the activity of caspases, the effector enzymes of cell death, by relieving the repression of caspases by the 'inhibitor of apoptosis' (IAP) proteins. It seems that Reaper, Hid and Grim compete with caspases for binding to IAPs; a function that requires the presence of the conserved amino terminus.

sickle was identified on the basis of its homology to reaper-family genes with respect to sequence, chromosomal location and expression. The sickle gene maps to chromosome 3L, just proximal to the reaper gene, and it is responsive to γ-radiation, as is the case for reaper. sickle expression is essentially restricted to specific regions of the head and central nervous system in developing Drosophila embryos, in areas where reaper and grim have been reported to be expressed. This suggests that Sickle might functionally interact with Reaper and Grim to regulate cell death in the central nervous system.

All three groups found that Sickle can induce cell death when overexpressed in mammalian or insect cells, and the Alnemri lab saw ectopic cell death when Sickle was overexpressed in Drosophila embryos. But as sickle is expressed in H99 mutants, which are largely defective in programmed cell death, it seems that its expression at physiological levels is not sufficient to induce cell death in most cell types. Indeed, unlike Reaper or Grim, when ectopically expressed in the Drosophila eye, Sickle alone was unable to induce cell death, but it did enhance Reaper- or Grim-induced cell death. Like other Reaper-family proteins, however, the Sickle gene product has a conserved amino-terminal end and a Trp block. Induction of apoptosis by Sickle is dependent on this conserved amino terminus, and it is inhibited by caspase inhibitors and IAPs.

How does Sickle regulate Reaper- and Grim-induced death? Does it simply contribute to titrating out IAPs? And what is Sickle's actual function in vivo? More insight into the genetic interaction between sickle and other cell-death-regulating genes in Drosophila is required to address these questions. Two proteins that seem to be functional homologues of Reaper-like proteins have recently been identified in mammals. These proteins — Smac/DIABLO and Omi/HtrA2 — also bear the conserved amino-terminal motif. However, their expression pattern and subcellular localization seem to be different from those of the Drosophila Reaper-like proteins, so further work is needed to establish whether they are true homologues.

ORIGINAL RESEARCH PAPERS

  1. 1

    Srinivasa, M. et al. sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein. Curr. Biol. 12, 125–130 (2002)

    Article  Google Scholar 

  2. 2

    Wing, J. P. et al. Drosophila sickle is a novel grim–reaper cell death activator. Curr. Biol. 12, 131–135 (2002)

    CAS  Article  Google Scholar 

  3. 3

    Christich, A. et al. The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper, grim, and hid. Curr. Biol. 12, 137–140 (2002)

    CAS  Article  Google Scholar 

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Ferrier, V. Grim, reaper and the sickle of death. Nat Rev Mol Cell Biol 3, 146 (2002). https://doi.org/10.1038/nrm751

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