skl encodes Sickle, a short Drosophila RHG-region IAP antagonist. Its exposed N-terminal IAP-binding motif binds BIR domains in DIAP1 and DIAP2 and thereby relieves IAP-mediated caspase inhibition, allowing apoptotic caspase activation together with Reaper, Hid, and Grim. Sickle is induced in several developmental and genotoxic contexts and usually acts as a potentiating RHG factor rather than as a lone death trigger, including Tao-1-dependent potentiation of Hid in Nanos-deficient pole cells and a minor, backup role alongside Grim in metamorphic corazonergic-neuron death.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005575 cellular_component | ND GO_REF:0000015 | ACCEPT | Summary: Sickle has no informative curated compartment annotation. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the cellular component is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: KEEP_AS_NON_CORE. |
| GO:0006915 apoptotic process | IDA PMID:11818065 The damage-responsive Drosophila gene sickle encodes a novel... | MODIFY | Summary: Sickle is an IAP-binding apoptosis activator, but its direct role is apoptotic signaling. Reason: Christich et al. showed that full-length Sickle induced apoptosis and that its N terminus bound DIAP1 BIR2. Mechanistically, Sickle acts upstream of caspase execution by antagonizing IAP inhibition, so apoptotic signaling pathway is more precise than top-level apoptotic process. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:11818065 full-length skl induced apoptosis when overexpressed, and the N terminus of this protein specifically bound to the BIR2 domain of DIAP1 |
| GO:0006915 apoptotic process | IGI PMID:11818063 sickle, a novel Drosophila death gene in the reaper/hid/grim... | MODIFY | Summary: Sickle cooperates with Grim to induce ectopic apoptotic signaling. Reason: Srinivasula et al. found that coexpressing Sickle and Grim in Drosophila eye discs enhanced ectopic cell death, consistent with Sickle acting as an IAP antagonist in the upstream apoptotic signaling module. That mechanism is narrower than generic apoptotic process. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:11818063 coexpression of Skl and Grim in the eye discs of transgenic flies results in a dramatic reduction of eye size |
| GO:0006915 apoptotic process | IGI PMID:11818064 Drosophila sickle is a novel grim-reaper cell death activato... | MODIFY | Summary: Sickle enhances Reaper/Rpr-driven cell death. Reason: The abstract-only Wing et al. paper reports that Sickle alone was weak in the fly eye but strongly enhanced Reaper-driven or Rpr/Grim-chimera-driven eye cell death. That is valid RHG-family apoptosis signaling and is more precise than top-level apoptotic process. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:11818064 sickle strongly enhanced the eye cell death induced by expression of either an r/grim chimera or reaper |
| GO:0006915 apoptotic process | IGI PMID:17449640 Maternal Nanos represses hid/skl-dependent apoptosis to main... | MODIFY | Summary: Tao-1-dependent Sickle potentiates Hid-dependent pole-cell apoptosis. Reason: Sato et al. placed Sickle downstream of maternal Tao-1 as a potentiator of Hid activity in Nanos-deficient pole cells. This is a contextual deployment of the RHG/IAP-antagonist apoptotic signaling module rather than a separate execution-step activity. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:17449640 Tao-1-dependent skl expression potentiates the activity of Hid to induce apoptosis in pole cells |
| GO:0006915 apoptotic process | IMP PMID:11818063 sickle, a novel Drosophila death gene in the reaper/hid/grim... | MODIFY | Summary: Ectopic Sickle promotes caspase-dependent apoptotic signaling. Reason: Full-length Sickle induced p35-sensitive apoptosis in Drosophila S2 cells and apoptosis in transgenic embryos, and the same paper showed N-terminal IBM-dependent IAP binding and IAP relief. The proximal activity is therefore apoptotic signaling pathway. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:11818063 many embryonic cells were induced to undergo apoptosis following skl expression PMID:11818063 Skl, like Smac/DIABLO, is able to disrupt the interaction of caspases with IAPs to promote caspase activation |
| GO:0006915 apoptotic process | IMP PMID:11818064 Drosophila sickle is a novel grim-reaper cell death activato... | MODIFY | Summary: Overexpressed Sickle triggers caspase-dependent death in insect cells. Reason: The Wing et al. abstract reports that Sickle-induced insect-cell death is antagonized by p35 or DIAP1, placing Sickle in the IAP/caspase apoptotic signaling pathway rather than at a downstream execution step. Proposed replacements: apoptotic signaling pathway Supporting Evidence: PMID:11818064 sickle very effectively induced cell death in cultured Spodoptera Sf-9 cells, and this death was antagonized by the caspase inhibitors p35 or DIAP1 |
| GO:0006915 apoptotic process | NAS DOI:10.1016/S0168-9525(02)02778-6 | UNDECIDED | Summary: The review-article NAS source is not cached locally. Reason: Sickle's participation in apoptosis is well established by primary papers, but this DOI-only NAS row cannot be checked against a local cached source, and the broad term is already handled by multiple experimental rows above. |
| GO:0010623 programmed cell death involved in cell development | IMP PMID:23519152 Essential role of grim-led programmed cell death for the est... | KEEP AS NON CORE | Summary: Sickle has a minor developmental programmed-cell-death role in corazonergic neurons. Reason: Choi et al. found that Grim is the major proapoptotic factor in this neuronal death program and that Sickle plays a milder backup role. The row is biologically supported, but it is a tissue/developmental output of Sickle's broader IAP-antagonist activity. Supporting Evidence: PMID:23519152 Mild PCD defect in the skl mutants also suggest that skl plays at least a minor role |
| GO:0071479 cellular response to ionizing radiation | IDA PMID:11818065 The damage-responsive Drosophila gene sickle encodes a novel... | UNDECIDED | Summary: Sickle is induced by genotoxic stimuli, but the cached abstract does not verify a Sickle protein role in a specific ionizing-radiation response. Reason: The abstract reports genotoxic induction of skl and frames Sickle as a candidate transducer of apoptotic damage signaling, but it does not expose the full irradiation assay or establish whether the gene product directly mediates ionizing-radiation-triggered apoptosis. Keep this unresolved until the Christich et al. full text can be checked. Supporting Evidence: PMID:11818065 Genotoxic stimuli induced skl expression |
| GO:1990525 BIR domain binding | IDA PMID:11818063 sickle, a novel Drosophila death gene in the reaper/hid/grim... | NEW | Summary: Sickle binds IAP BIR domains through its N-terminal IAP-binding motif. Reason: Direct in vitro binding and DIAP1-BIR2 cocrystal evidence show that Sickle's N-terminal IBM binds the DIAP1 BIR2 surface and Drosophila DIAP2 BIR3, which is the molecular-function step that explains its apoptotic signaling activity. Supporting Evidence: PMID:11818063 Skl, like Grim and Smac/DIABLO, was able to interact strongly and specifically with either of the full-length proteins or with the BIR2 of DIAP1 or BIR3 of DIAP2 PMID:11818063 The N-Terminal Tetrapeptide of Skl Binds a Conserved Surface Groove on DIAP1-BIR2 |
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Download this section (compressed HTML)Q: Should FlyBase add an experimental `BIR domain binding` assertion for Sickle from the DIAP1-BIR2 structural and binding data, mirroring the more specific BIR-domain annotations on other Drosophila RHG proteins?
Q: Which endogenous apoptotic tissues require Sickle uniquely rather than as a potentiator of Grim, Hid, or Reaper?
Experiment: Use CRISPR replacement at the endogenous skl locus to compare a clean null with N-terminal IBM point mutants in pole-cell, vCrz-neuron, embryonic CNS, and genotoxic-stress apoptosis assays; quantify DIAP1 occupancy, active DrICE/Dcp-1, and genetic synergy with grim, hid, and rpr.
Experiment: Image a functional endogenously tagged Sickle protein during damage-induced and developmental apoptosis to determine whether Sickle remains cytosolic, concentrates at DIAP1/caspase complexes, or uses a distinct subcellular pool from Reaper/Grim GH3-family mitochondrial antagonists.
sickle (skl) encodes a member of the inhibitor of apoptotic protein antagonists. It is partially involved in the apoptosis of some larval neurons during metamorphosis.
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