Mouse DIABLO/SMAC is a mitochondrial IAP antagonist whose processed N-terminal motif and dimeric binding surfaces engage BIR-containing inhibitor-of-apoptosis proteins. Release of mature protein from the mitochondrial intermembrane space permits cytosolic antagonism of XIAP and facilitates caspase activation and activity. It does not itself cleave caspase substrates. Its contribution is stimulus- and cell-dependent: mouse myogenic and neuronal studies support apoptotic roles, while endogenous release is insufficient to overcome XIAP in some sympathetic-neuron conditions. SMAC can also associate with activated CD40 complexes in B cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:23479728 Identification of a novel anti-apoptotic E3 ubiquitin ligase... | REMOVE | Summary: AREL1 association is an interaction/substrate relationship. Reason: The source reports AREL1 association with apoptosis regulators. Remove uninformative bare protein binding under policy while retaining the observation; DIABLO is not assigned AREL1 ubiquitin-ligase activity. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:15882989 MEKK1-induced apoptosis is mediated by Smac/Diablo release f... | MODIFY | Summary: Released SMAC enters the cytosol. Reason: Mouse cell experiments detect mitochondrial-to-cytoplasmic redistribution during apoptotic stimulation; the established soluble released pool supports the more specific cytosolic location. This is localization, not a claim that release alone suffices for death. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IDA PMID:16085184 Role of Smac/DIABLO in hydrogen peroxide-induced apoptosis i... | MODIFY | Summary: Released SMAC enters the cytosol. Reason: Mouse cell experiments detect mitochondrial-to-cytoplasmic redistribution during apoptotic stimulation; the established soluble released pool supports the more specific cytosolic location. This is localization, not a claim that release alone suffices for death. Proposed replacements: cytosol |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: This HDA annotation comes from the mouse mitochondrial proteomic survey across brain, heart, kidney and liver. The cached source is abstract-only, so no new target-specific peptide or topology claim is made from it. Retain the curator-supported mitochondrial detection, corroborated independently by mouse SMAC localization/release and import experiments. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: The MitoCarta study combines mass spectrometry, GFP tagging and integrative evidence across 14 mouse tissues to establish a mitochondrial inventory. Its organelle-resolution annotation is consistent with independent mouse SMAC localization/import evidence; inventory inclusion does not itself resolve IMS topology. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: The PAINT mitochondrial inference at PTN001283560 is supported by mouse and human experimental grounding and agrees with direct mouse localization/release studies. Inclusion of the target among descendant sources is legitimate, not circular. There is no evidence here of loss of mitochondrial targeting or a misplaced ancestral assertion. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IDA PMID:14623868 Critical function of endogenous XIAP in regulating caspase a... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: Full-text Figure 7 in PMID:14623868 shows punctate mitochondrial endogenous Smac staining in mouse sympathetic neurons and loss of that staining after H2O2 treatment. This directly supports mitochondrial localization and stimulus-dependent release. The failure of released endogenous Smac to overcome XIAP in this neuronal setting limits its functional sufficiency, not its localization. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IDA PMID:15814844 Mature DIABLO/Smac is produced by the IMP protease complex o... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: PMID:15814844 explicitly uses full-length mouse DIABLO in import/processing experiments, including a heterologous yeast system. The study supports mitochondrial targeting and processing with an IMS mature pool; the historical IMP-processing model is not treated as proof that every native mammalian context uses the same protease. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IDA PMID:15882989 MEKK1-induced apoptosis is mediated by Smac/Diablo release f... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: The cached abstract of PMID:15882989 reports mitochondrial Smac/Diablo release and explicitly includes mouse embryonic fibroblast experiments on MEKK1-dependent release. Retain the experimental organelle assignment. The abstract does not provide submitochondrial topology or justify a new universal signaling mechanism. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IDA PMID:16085184 Role of Smac/DIABLO in hydrogen peroxide-induced apoptosis i... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: PMID:16085184 explicitly reports Western-blot detection of Smac/DIABLO translocation from mitochondria to cytoplasm in C2C12 myogenic cells after H2O2 treatment. This supports mitochondrial residence and stimulus-dependent release; the abstract-only cache does not independently resolve IMS topology. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: The InterPro Smac/DIABLO family and fold mappings plus UniProt mitochondrial location mapping are consistent with directly characterized mouse targeting and release. These independent target observations support the organelle claim without treating an electronic location line as its own experimental evidence. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: Transfer from characterized human DIABLO Q9NR28 is consistent with conserved mitochondrial targeting and independent mouse localization/import experiments. Retain the correct mitochondrial orthology inference; source-specific subcompartment and processing details are assessed separately. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005739 mitochondrion | ISS PMID:18385140 Dual specificity phosphatases 18 and 21 target to opposing s... | ACCEPT | Summary: Mitochondrial localization is supported and remains informative at organelle resolution. Reason: The full text of PMID:18385140 uses SMAC as a mitochondrial and IMS marker during rat kidney mitochondrial purification and subfractionation. This is comparative localization evidence, not a direct mouse assay; its conserved organelle assignment agrees with independent mouse SMAC targeting and release experiments. The paper’s main focus on DSP18/DSP21 does not negate the assayed SMAC marker. Retain the informative mitochondrion assertion under the root-organelle policy; supported intermembrane-space annotations remain separate. |
| GO:0005758 mitochondrial intermembrane space | ISO PMID:17376863 MitoNEET is an iron-containing outer mitochondrial membrane ... | ACCEPT | Summary: The mature pre-release pool resides in the mitochondrial intermembrane space. Reason: Import and release studies and submitochondrial fractionation support IMS residence. Papers centered on other mitochondrial proteins can use SMAC as a compartment marker; that is relevant localization evidence rather than gene misattribution. |
| GO:0005758 mitochondrial intermembrane space | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | ACCEPT | Summary: The mature pre-release pool resides in the mitochondrial intermembrane space. Reason: Import and release studies and submitochondrial fractionation support IMS residence. Papers centered on other mitochondrial proteins can use SMAC as a compartment marker; that is relevant localization evidence rather than gene misattribution. |
| GO:0005814 centriole | ISO GO_REF:0000119 | UNDECIDED | Summary: The specific imported centriole or sperm-subcompartment localization requires its donor experiment. Reason: The available discovery, mitochondrial-processing and neuronal studies do not resolve this precise compartment. The ISO assertion is preserved; lack of verification is not evidence that the location is false. No independent native mouse localization experiment was recovered for this exact term. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9NR28 UNRESOLVED The donor exact compartment experiment was not recovered in the available source review; preserve uncertainty rather than claiming erroneous transfer. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Released mature DIABLO acts in the cytosol. Reason: The original discovery identifies processed DIABLO in cytosolic fractions after UV irradiation, and mouse cellular studies show stimulus-dependent redistribution. Cytosol is the compartment for IAP antagonism, not a statement that mitochondrial release invariably overcomes XIAP. |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: Released mature DIABLO acts in the cytosol. Reason: The original discovery identifies processed DIABLO in cytosolic fractions after UV irradiation, and mouse cellular studies show stimulus-dependent redistribution. Cytosol is the compartment for IAP antagonism, not a statement that mitochondrial release invariably overcomes XIAP. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Released mature DIABLO acts in the cytosol. Reason: The original discovery identifies processed DIABLO in cytosolic fractions after UV irradiation, and mouse cellular studies show stimulus-dependent redistribution. Cytosol is the compartment for IAP antagonism, not a statement that mitochondrial release invariably overcomes XIAP. |
| GO:0006915 apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: DIABLO contributes to intrinsic apoptotic signaling through IAP antagonism. Reason: The performed step is antagonism of inhibitory IAP proteins, allowing caspase activation/activity. Refine broad apoptosis/signaling to the existing intrinsic-pathway term; DIABLO neither catalyzes caspase cleavage nor merely serves as a consumed substrate. Proposed replacements: intrinsic apoptotic signaling pathway |
| GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mouse DIABLO participates in peroxide-induced apoptotic signaling in myogenic cells. Reason: PMID:16085184 reports mitochondrial release and reciprocal overexpression/antisense effects on apoptosis and caspase activation in C2C12 cells. Retain the direct and inherited claims consistently with the specific oxidative-stress context; no universal stress-sensor activity is implied. Supporting Evidence: |
| GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress | IDA PMID:16085184 Role of Smac/DIABLO in hydrogen peroxide-induced apoptosis i... | KEEP AS NON CORE | Summary: Mouse DIABLO participates in peroxide-induced apoptotic signaling in myogenic cells. Reason: PMID:16085184 reports mitochondrial release and reciprocal overexpression/antisense effects on apoptosis and caspase activation in C2C12 cells. Retain the direct and inherited claims consistently with the specific oxidative-stress context; no universal stress-sensor activity is implied. Supporting Evidence: |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:20614026 HOIL-1L interacting protein (HOIP) as an NF-kappaB regulatin... | KEEP AS NON CORE | Summary: SMAC associates with activated CD40 receptor assemblies in mouse B cells. Reason: PMID:20614026 identifies endogenous SMAC in receptor capture/MS/immunoblot experiments, with TRAF2 and receptor-tail controls. This supports a contextual cytoplasmic membrane-side/co-complex location, not direct SMAC-CD40 binding or an integral membrane topology. Supporting Evidence: |
| GO:0035631 CD40 receptor complex | IDA PMID:20614026 HOIL-1L interacting protein (HOIP) as an NF-kappaB regulatin... | KEEP AS NON CORE | Summary: SMAC associates with activated CD40 receptor assemblies in mouse B cells. Reason: PMID:20614026 identifies endogenous SMAC in receptor capture/MS/immunoblot experiments, with TRAF2 and receptor-tail controls. This supports a contextual cytoplasmic membrane-side/co-complex location, not direct SMAC-CD40 binding or an integral membrane topology. Supporting Evidence: |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000117 | MODIFY | Summary: SMAC positively regulates intrinsic apoptotic signaling by antagonizing IAPs. Reason: The discovery and biochemical reconstitution establish relief of XIAP inhibition of caspase activation/activity. GO:2001244 retains the positive regulatory sign while refining the process. Human purified-SMAC reconstitution is mechanistic ortholog support; the mouse discovery and cell experiments support native biological relevance. Proposed replacements: positive regulation of intrinsic apoptotic signaling pathway |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:11604410 HtrA2 promotes cell death through its serine protease activi... | MODIFY | Summary: SMAC positively regulates intrinsic apoptotic signaling by antagonizing IAPs. Reason: The discovery and biochemical reconstitution establish relief of XIAP inhibition of caspase activation/activity. GO:2001244 retains the positive regulatory sign while refining the process. Human purified-SMAC reconstitution is mechanistic ortholog support; the mouse discovery and cell experiments support native biological relevance. Proposed replacements: positive regulation of intrinsic apoptotic signaling pathway |
| GO:0043065 positive regulation of apoptotic process | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | MODIFY | Summary: SMAC positively regulates intrinsic apoptotic signaling by antagonizing IAPs. Reason: The discovery and biochemical reconstitution establish relief of XIAP inhibition of caspase activation/activity. GO:2001244 retains the positive regulatory sign while refining the process. Human purified-SMAC reconstitution is mechanistic ortholog support; the mouse discovery and cell experiments support native biological relevance. Proposed replacements: positive regulation of intrinsic apoptotic signaling pathway |
| GO:0051402 neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: DIABLO can promote neuronal apoptosis when supplied at an effective level. Reason: PMID:14623868 tests recombinant SMAC plus cytochrome c with an IAP-binding-motif control in mouse sympathetic neurons. Endogenous SMAC release alone is insufficient in the tested wild-type neurons. Retain conditional participation without converting the exogenous rescue into universal endogenous sufficiency. Supporting Evidence: |
| GO:0051402 neuron apoptotic process | IDA PMID:14623868 Critical function of endogenous XIAP in regulating caspase a... | KEEP AS NON CORE | Summary: DIABLO can promote neuronal apoptosis when supplied at an effective level. Reason: PMID:14623868 tests recombinant SMAC plus cytochrome c with an IAP-binding-motif control in mouse sympathetic neurons. Endogenous SMAC release alone is insufficient in the tested wild-type neurons. Retain conditional participation without converting the exogenous rescue into universal endogenous sufficiency. Supporting Evidence: |
| GO:0097190 apoptotic signaling pathway | ISO GO_REF:0000119 | MODIFY | Summary: DIABLO contributes to intrinsic apoptotic signaling through IAP antagonism. Reason: The performed step is antagonism of inhibitory IAP proteins, allowing caspase activation/activity. Refine broad apoptosis/signaling to the existing intrinsic-pathway term; DIABLO neither catalyzes caspase cleavage nor merely serves as a consumed substrate. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9NR28 SUPPORTS TRANSFER The original broader claim is retained as biologically supported. Target/ortholog evidence refines its scope; this does not reject the ancestral placement or treat target experimental grounding as circular. Proposed replacements: intrinsic apoptotic signaling pathway |
| GO:0097193 intrinsic apoptotic signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: IAP antagonism is DIABLO participation in intrinsic apoptotic signaling. Reason: Processed DIABLO directly opposes IAP suppression of the caspase pathway. This is an active molecular contribution, not an inference from being released by mitochondria. The effect depends on mature motif exposure and effective antagonist concentration. |
| GO:0097193 intrinsic apoptotic signaling pathway | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | ACCEPT | Summary: IAP antagonism is DIABLO participation in intrinsic apoptotic signaling. Reason: Processed DIABLO directly opposes IAP suppression of the caspase pathway. This is an active molecular contribution, not an inference from being released by mitochondria. The effect depends on mature motif exposure and effective antagonist concentration. |
| GO:0097225 sperm midpiece | ISO GO_REF:0000119 | UNDECIDED | Summary: The specific imported centriole or sperm-subcompartment localization requires its donor experiment. Reason: The available discovery, mitochondrial-processing and neuronal studies do not resolve this precise compartment. The ISO assertion is preserved; lack of verification is not evidence that the location is false. No independent native mouse localization experiment was recovered for this exact term. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9NR28 UNRESOLVED The donor exact compartment experiment was not recovered in the available source review; preserve uncertainty rather than claiming erroneous transfer. |
| GO:0097228 sperm principal piece | ISO GO_REF:0000119 | UNDECIDED | Summary: The specific imported centriole or sperm-subcompartment localization requires its donor experiment. Reason: The available discovery, mitochondrial-processing and neuronal studies do not resolve this precise compartment. The ISO assertion is preserved; lack of verification is not evidence that the location is false. No independent native mouse localization experiment was recovered for this exact term. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9NR28 UNRESOLVED The donor exact compartment experiment was not recovered in the available source review; preserve uncertainty rather than claiming erroneous transfer. |
| GO:0097229 sperm end piece | ISO GO_REF:0000119 | UNDECIDED | Summary: The specific imported centriole or sperm-subcompartment localization requires its donor experiment. Reason: The available discovery, mitochondrial-processing and neuronal studies do not resolve this precise compartment. The ISO assertion is preserved; lack of verification is not evidence that the location is false. No independent native mouse localization experiment was recovered for this exact term. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9NR28 UNRESOLVED The donor exact compartment experiment was not recovered in the available source review; preserve uncertainty rather than claiming erroneous transfer. |
| GO:1990713 survivin complex | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: The imported BIR-containing antiapoptotic-complex association is retained contextually. Reason: The source human term definition includes a BIR-family antiapoptotic complex and cites PMID:19153467, whose SMAC-peptide/BIRC2-BIR3 system supports that broad definition. Retain the ortholog inference with this limited construct/context; it does not demonstrate a stable endogenous mouse full-length BIRC5 assembly. Supporting Evidence: |
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