Mouse XIAP is a BIR-domain and RING-domain protein that inhibits apoptotic caspases and catalyzes ubiquitin transfer. Conserved BIR2/linker and BIR3 mechanisms restrain caspases-3/7 and caspase-9, respectively. Its RING-dependent ubiquitination supports NOD1/NOD2-RIPK2 innate immune signaling and other substrate-dependent outputs, including Wnt regulation. Cytoplasmic and nuclear pools serve distinct contexts. Endogenous XIAP regulates neuronal resistance to cytochrome c, Fas-dependent hepatocyte apoptosis, and intestinal crypt survival; these effects depend on cell type and the balance of XIAP antagonists.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002020 protease binding | ISO GO_REF:0000096 | MODIFY | Summary: Mouse Xiap directly inhibits cysteine-type endopeptidases (caspases); the row is modified to cysteine-type endopeptidase inhibitor activity, with the apoptotic context carried by the module and core functions. Reason: The replacement is the genus rather than the precomposed GO:0043027 (projects/INVOLVED_IN_PRECOMPOSITION.md); the apoptotic context is carried by the module apoptotic_execution_phase#xiap_caspase_inhibitor and the core functions. Earlier reasoning, retained for its evidence (its replacement updated to the genus): Conserved XIAP BIR architecture and mouse caspase-3/death assays support the endopeptidase-inhibitor function. Refine the broad binding/inhibitor assertion; human BIR3 structural work is ortholog evidence, not a direct mouse structure. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:620692 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: cysteine-type endopeptidase inhibitor activity |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000107 | MODIFY | Summary: XIAP RING-domain ubiquitin transfer is better captured by ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: The seeded term or process is a broad proxy for XIAP's catalytic RING E3 activity. Replace it with GO:0061630, the specific ubiquitin protein ligase molecular function supported by direct XIAP substrate-ubiquitination studies. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Proposed replacements: ubiquitin protein ligase activity |
| GO:0004842 ubiquitin-protein transferase activity | ISO GO_REF:0000119 | MODIFY | Summary: XIAP RING-domain ubiquitin transfer is better captured by ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: The seeded term or process is a broad proxy for XIAP's catalytic RING E3 activity. Replace it with GO:0061630, the specific ubiquitin protein ligase molecular function supported by direct XIAP substrate-ubiquitination studies. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P98170 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: ubiquitin protein ligase activity |
| GO:0004842 ubiquitin-protein transferase activity | ISS GO_REF:0000024 | MODIFY | Summary: XIAP RING-domain ubiquitin transfer is better captured by ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: The seeded term or process is a broad proxy for XIAP's catalytic RING E3 activity. Replace it with GO:0061630, the specific ubiquitin protein ligase molecular function supported by direct XIAP substrate-ubiquitination studies. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Proposed replacements: ubiquitin protein ligase activity |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse Xiap directly inhibits cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. Reason: The genus GO:0004869 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0043027; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module apoptotic_execution_phase#xiap_caspase_inhibitor and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: Conserved XIAP BIR architecture and mouse caspase-3/death assays support the specific apoptotic endopeptidase-inhibitor function. Refine the broad binding/inhibitor assertion; human BIR3 structural work is ortholog evidence, not a direct mouse structure. |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse Xiap directly inhibits cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. Reason: The genus GO:0004869 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0043027; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module apoptotic_execution_phase#xiap_caspase_inhibitor and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: Conserved XIAP BIR architecture and mouse caspase-3/death assays support the specific apoptotic endopeptidase-inhibitor function. Refine the broad binding/inhibitor assertion; human BIR3 structural work is ortholog evidence, not a direct mouse structure. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98170 SUPPORTS TRANSFER Human XIAP's caspase inhibitor activity transfers to mouse Xiap at the right granularity; the genus GO:0004869 is as precise as warranted, with the apoptotic context carried by the module and core functions. |
| GO:0005515 protein binding | IPI PMID:11604410 HtrA2 promotes cell death through its serine protease activi... | REMOVE | Summary: The reported interaction is retained as evidence but generic binding is uninformative. Reason: HtrA2 binding antagonizes XIAP; it does not make XIAP a serine protease. Remove only GO:0005515 under the current binding policy, without disputing the association or transferring the partner enzyme activity to XIAP. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16858406 Unique anti-apoptotic activity of EAAC1 in injured motor neu... | REMOVE | Summary: The reported interaction is retained as evidence but generic binding is uninformative. Reason: HCCS-XIAP association can be opposed by EAAC1 in neuronal survival assays. Remove only GO:0005515 under the current binding policy, without disputing the association or transferring the partner enzyme activity to XIAP. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19268530 NRAGE: a potential rheostat during branching morphogenesis. | REMOVE | Summary: The reported interaction is retained as evidence but generic binding is uninformative. Reason: The full text identifies XIAP in the NRAGE/TAK1/TAB1 co-immunoprecipitated assembly from mIMCD-3 cells; this does not establish a binary direct contact. Remove only GO:0005515 under the current binding policy, without disputing the association or transferring the partner enzyme activity to XIAP. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:30389919 ARTS mediates apoptosis and regeneration of the intestinal s... | REMOVE | Summary: The reported interaction is retained as evidence but generic binding is uninformative. Reason: ARTS/Sept4 association opposes XIAP in intestinal crypt survival. Remove only GO:0005515 under the current binding policy, without disputing the association or transferring the partner enzyme activity to XIAP. Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MODIFY | Summary: Supported nuclear subcompartments refine the broad nuclear assignment. Reason: The gene has independently supported nucleoplasmic Wnt-regulatory localization and a curated HPA nucleolar observation. Refine the broad nucleus assertion to both supported compartments; this does not require a separate nucleolar biochemical activity or assign the same compartment to every experimental condition. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000005166 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: nucleoplasm nucleolus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | MODIFY | Summary: Supported nuclear subcompartments refine the broad nuclear assignment. Reason: The gene has independently supported nucleoplasmic Wnt-regulatory localization and a curated HPA nucleolar observation. Refine the broad nucleus assertion to both supported compartments; this does not require a separate nucleolar biochemical activity or assign the same compartment to every experimental condition. Proposed replacements: nucleoplasm nucleolus |
| GO:0005634 nucleus | ISO GO_REF:0000119 | MODIFY | Summary: Supported nuclear subcompartments refine the broad nuclear assignment. Reason: The gene has independently supported nucleoplasmic Wnt-regulatory localization and a curated HPA nucleolar observation. Refine the broad nucleus assertion to both supported compartments; this does not require a separate nucleolar biochemical activity or assign the same compartment to every experimental condition. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P98170 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: nucleoplasm nucleolus |
| GO:0005634 nucleus | ISS GO_REF:0000024 | MODIFY | Summary: Supported nuclear subcompartments refine the broad nuclear assignment. Reason: The gene has independently supported nucleoplasmic Wnt-regulatory localization and a curated HPA nucleolar observation. Refine the broad nucleus assertion to both supported compartments; this does not require a separate nucleolar biochemical activity or assign the same compartment to every experimental condition. Proposed replacements: nucleoplasm nucleolus |
| GO:0005654 nucleoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP has curated cytoplasmic or nuclear localization, but this location row is broader than its molecular roles. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. |
| GO:0005654 nucleoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP has curated cytoplasmic or nuclear localization, but this location row is broader than its molecular roles. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. |
| GO:0005730 nucleolus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nucleolar localization is retained as a contextual observation. Reason: Mouse ortholog assessment: The HPA localization assertion concerns presence, not a requirement to demonstrate a separate nucleolar biochemical function. There is no contradictory localization evidence; retain the curated imaging observation without making nucleolar activity a core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0005730 nucleolus | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Nucleolar localization is retained as a contextual observation. Reason: Mouse ortholog assessment: The HPA localization assertion concerns presence, not a requirement to demonstrate a separate nucleolar biochemical function. There is no contradictory localization evidence; retain the curated imaging observation without making nucleolar activity a core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:15737931 The Sept4 septin locus is required for sperm terminal differ... | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: XIAP has a functional cytoplasmic pool. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: The cytosolic XIAP pool restrains caspase activation. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0005829 cytosol | ISO GO_REF:0000119 | ACCEPT | Summary: The cytosolic XIAP pool restrains caspase activation. Reason: XIAP functions in cytoplasmic/cytosolic caspase and signaling assemblies and in nucleoplasmic TLE/TCF regulation. Retain this supported compartment at the resolution of the original experiment or ortholog inference; soluble versus assembled pools and nuclear translocation do not establish a single exclusive location. PMID:22304967 supports the nuclear signaling pool and PMID:11257230 the caspase-inhibitor mechanism. Supporting Evidence: |
| GO:0006974 DNA damage response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: XIAP contributes to a survival response after DNA damage. Reason: Mouse ortholog assessment: PMID:18049476 places XIAP downstream of Che-1/NF-kappaB and reports XIAP expression is necessary for the antiapoptotic activity. A response-to-damage term does not require DNA repair catalysis. Retain the stress-dependent survival response without assigning XIAP a repair enzyme or damage-sensor role. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: |
| GO:0010804 negative regulation of tumor necrosis factor-mediated signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: XIAP attenuates the apoptotic branch of TNF signaling. Reason: Mouse ortholog assessment: The GO definition covers a decrease in rate or extent of TNF-mediated signaling; it does not require inhibition of every downstream branch. XIAP protects against TNF-induced apoptosis through caspase inhibition and TAK1/JNK-dependent survival signaling. This context can coexist with positive NF-kappaB/JNK regulation. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: |
| GO:0031398 positive regulation of protein ubiquitination | IBA GO_REF:0000033 | MODIFY | Summary: XIAP promotes LUBAC-dependent linear ubiquitination. Reason: Mouse ortholog assessment: XIAP both catalyzes substrate ubiquitination and recruits another ligase, LUBAC, to NOD2/RIPK2 complexes. Refine positive regulation of protein ubiquitination to the already represented linear-polyubiquitination control process. This retains the regulatory process rather than replacing a BP with E3 molecular activity; XIAP is not itself assigned linear-chain synthesis. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000799425 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: positive regulation of protein linear polyubiquitination Supporting Evidence: |
| GO:0031398 positive regulation of protein ubiquitination | IEA GO_REF:0000107 | MODIFY | Summary: XIAP promotes LUBAC-dependent linear ubiquitination. Reason: Mouse ortholog assessment: XIAP both catalyzes substrate ubiquitination and recruits another ligase, LUBAC, to NOD2/RIPK2 complexes. Refine positive regulation of protein ubiquitination to the already represented linear-polyubiquitination control process. This retains the regulatory process rather than replacing a BP with E3 molecular activity; XIAP is not itself assigned linear-chain synthesis. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Proposed replacements: positive regulation of protein linear polyubiquitination Supporting Evidence: |
| GO:0032481 positive regulation of type I interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: XIAP has a non-apoptotic interferon-regulatory role through the XAF1/IRF7 axis. Reason: Mouse ortholog assessment: The XAF1 study and GO-CAM place XIAP E3-ligase activity upstream of IRF7 and type-I-interferon production; this is direct but outside apoptosis. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:36394357 XAF1 is associated specifically with IRF7 and inhibits the activity of XIAP. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:35263589 Nociceptor-derived Reg3Ξ³ prevents endotoxic death by targeti... | UNDECIDED | Summary: The LPS-specific source experiment remains unresolved. Reason: PMID:35263589 is the actual mouse experimental source. Its accessible abstract does not expose the XIAP-specific LPS experiment, and targeted source searching did not recover it. Retain UNDECIDED pending that result; absence from the abstract is not evidence of curator misattribution. Supporting Evidence: |
| GO:0032991 protein-containing complex | ISO GO_REF:0000096 | MODIFY | Summary: The supported caspase-inhibitor assembly refines the broad complex location. Reason: Mouse ortholog assessment: XIAP is a physical component of experimentally characterized caspase-inhibitor complexes. The broad protein-containing-complex claim is correct and is refined to the existing specific complex, not removed as redundant. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: RGD:620692 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: protease inhibitor complex Supporting Evidence: |
| GO:0042742 defense response to bacterium | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP contributes enzymatically to antibacterial innate signaling. Reason: Mouse ortholog assessment: XIAP-mediated RIPK2 ubiquitination supports NOD1/NOD2 recognition pathways and downstream inflammatory signaling. This is performed defense-response work, not merely correlation with infection. Retain the defense process alongside its more mechanistic pathway annotations. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP self-association is supported by structural and biochemical evidence. Reason: Mouse ortholog assessment: Identical-protein binding captures supported XIAP homomeric association, including functionally important RING assembly. The special removal policy for bare GO:0005515 does not apply to this specific binding term. Retain the original experiment and its construct context. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP self-association is supported by structural and biochemical evidence. Reason: Mouse ortholog assessment: Identical-protein binding captures supported XIAP homomeric association, including functionally important RING assembly. The special removal policy for bare GO:0005515 does not apply to this specific binding term. Retain the original experiment and its construct context. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: PAINT inference of the core XIAP caspase inhibitor activity; the row is modified to the genus cysteine-type endopeptidase inhibitor activity, with the apoptotic context carried by the module and core functions. Reason: The precomposed GO:0043027 is replaced by its genus GO:0004869 (projects/INVOLVED_IN_PRECOMPOSITION.md); the activity is unchanged and the apoptotic context is carried by the module apoptotic_execution_phase#xiap_caspase_inhibitor and the core functions (see decomposed_into). The PAINT propagation itself is sound. Mouse ortholog assessment: BIR-mediated inhibition of caspase-3, caspase-7, and caspase-9 is a conserved, experimentally grounded XIAP function. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000953271 SUPPORTS TRANSFER The IAP node supports the caspase inhibitor activity, which is core for XIAP; the MODIFY only decomposes the precomposed term to its genus and does not dispute the transfer. Proposed replacements: cysteine-type endopeptidase inhibitor activity Context of precomposed term: module apoptotic_execution_phase / xiap_caspase_inhibitor in core functions Decomposed from the precomposed GO:0043027 (projects/INVOLVED_IN_PRECOMPOSITION.md) to its genus GO:0004869; the claim is unchanged and the apoptotic context is carried by the module apoptotic_execution_phase#xiap_caspase_inhibitor and this review's core functions. Mouse Xiap (UniProtKB:Q60989) is itself a representative member of that element's XIAP subfamily, alongside human XIAP. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: Mouse XIAP directly restrains apoptotic caspase activity and death. Reason: Mouse neuro2a experiments show XIAP-dependent inhibition of caspase-3 and death, while sympathetic neurons and Fas-stimulated hepatocytes demonstrate context-dependent endogenous protection. These results support negative regulation without claiming a universal tissue requirement or direct inhibition of caspase-6. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:12153481 X-Linked inhibitor of apoptosis protein is involved in mutan... | ACCEPT | Summary: Mouse XIAP directly restrains apoptotic caspase activity and death. Reason: Mouse neuro2a experiments show XIAP-dependent inhibition of caspase-3 and death, while sympathetic neurons and Fas-stimulated hepatocytes demonstrate context-dependent endogenous protection. These results support negative regulation without claiming a universal tissue requirement or direct inhibition of caspase-6. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: Mouse XIAP directly restrains apoptotic caspase activity and death. Reason: Mouse neuro2a experiments show XIAP-dependent inhibition of caspase-3 and death, while sympathetic neurons and Fas-stimulated hepatocytes demonstrate context-dependent endogenous protection. These results support negative regulation without claiming a universal tissue requirement or direct inhibition of caspase-6. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000096 | ACCEPT | Summary: Mouse XIAP directly restrains apoptotic caspase activity and death. Reason: Mouse neuro2a experiments show XIAP-dependent inhibition of caspase-3 and death, while sympathetic neurons and Fas-stimulated hepatocytes demonstrate context-dependent endogenous protection. These results support negative regulation without claiming a universal tissue requirement or direct inhibition of caspase-6. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP positively regulates canonical NF-kappaB signaling downstream of NOD receptors. Reason: Mouse ortholog assessment: RIPK2 ubiquitination and LUBAC recruitment promote the signaling complex that activates NF-kappaB. The positive-control process is biologically supported; replacing it with ubiquitination or pathway membership alone would lose its regulatory meaning. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: XIAP positively regulates canonical NF-kappaB signaling downstream of NOD receptors. Reason: Mouse ortholog assessment: RIPK2 ubiquitination and LUBAC recruitment promote the signaling complex that activates NF-kappaB. The positive-control process is biologically supported; replacing it with ubiquitination or pathway membership alone would lose its regulatory meaning. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0043524 negative regulation of neuron apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: XIAP suppresses neuronal apoptosis in defined settings. Reason: Mouse neuronal experiments directly establish the antiapoptotic role. Native XIAP resistance downstream of cytochrome c can remain despite endogenous SMAC release; this is tissue-contextual regulation rather than an invariant property of all neuronal states. |
| GO:0046330 positive regulation of JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: XIAP can activate TAK1/JNK signaling as a non-core survival branch. Reason: Mouse ortholog assessment: PMID:11865055 supports XIAP/TAB1/TAK1-dependent JNK activation in an overexpression survival system; this is peripheral to the direct caspase-inhibitor activity. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: The imported perinuclear localization is retained with curator deference. Reason: The ISO assignment is compatible with the cytoplasmic XIAP distribution; no evidence contradicts it. This specific location is retained as non-core without inferring an organelle-specific biochemical activity. |
| GO:0051402 neuron apoptotic process | IMP PMID:14623868 Critical function of endogenous XIAP in regulating caspase a... | KEEP AS NON CORE | Summary: XIAP participates as an inhibitor within the neuronal apoptotic response. Reason: PMID:14623868 demonstrates XIAP-dependent resistance of sympathetic neurons to cytosolic cytochrome c. The broad neuron-apoptosis term does not specify a positive sign; retain its supported inhibitory participation alongside negative regulation, rather than reading it as a proapoptotic claim. Supporting Evidence: |
| GO:0051726 regulation of cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: XIAP can control cell-cycle progression through its RING-dependent signaling activity. Reason: Mouse ortholog assessment: PMID:23720779 reports reduced cyclin D1 expression and cell-cycle transition in XIAP-deficient human cancer cells, with a requirement for XIAP E3 function in PP2A/c-Jun regulation. This target evidence supports a contextual cell-cycle role and gives no basis to reject the PAINT ancestral placement merely because other IAPs also regulate the cell cycle. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: |
| GO:0060785 regulation of apoptosis involved in tissue homeostasis | IMP PMID:30389919 ARTS mediates apoptosis and regeneration of the intestinal s... | KEEP AS NON CORE | Summary: Endogenous XIAP regulates intestinal crypt apoptosis and homeostasis. Reason: PMID:30389919 tests genetic Xiap loss in the ARTS/Sept4 context, linking XIAP inhibition to crypt stem/Paneth-cell survival and regenerative phenotypes. Retain this native mouse tissue role, distinct from a universal requirement in all tissues. Supporting Evidence: |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: XIAP has intrinsic RING-domain ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: XIAP is a bona fide RING E3 ubiquitin ligase that ubiquitinates multiple substrates, including PTEN, CCS, RIPK2, Groucho/TLE proteins, IRF7-pathway components, and BCL2 in different contexts. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:20154138 We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: XIAP has intrinsic RING-domain ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: XIAP is a bona fide RING E3 ubiquitin ligase that ubiquitinates multiple substrates, including PTEN, CCS, RIPK2, Groucho/TLE proteins, IRF7-pathway components, and BCL2 in different contexts. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:20154138 We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP |
| GO:0061630 ubiquitin protein ligase activity | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP has intrinsic RING-domain ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: XIAP is a bona fide RING E3 ubiquitin ligase that ubiquitinates multiple substrates, including PTEN, CCS, RIPK2, Groucho/TLE proteins, IRF7-pathway components, and BCL2 in different contexts. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:20154138 We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP |
| GO:0061630 ubiquitin protein ligase activity | ISS GO_REF:0000024 | ACCEPT | Summary: XIAP has intrinsic RING-domain ubiquitin protein ligase activity. Reason: Mouse ortholog assessment: XIAP is a bona fide RING E3 ubiquitin ligase that ubiquitinates multiple substrates, including PTEN, CCS, RIPK2, Groucho/TLE proteins, IRF7-pathway components, and BCL2 in different contexts. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:20154138 We also find that CCS is a target of the E3 ubiquitin ligase activity of XIAP |
| GO:0070427 nucleotide-binding oligomerization domain containing 1 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP acts directly in NOD1 signaling through RIPK2 ubiquitination. Reason: Mouse ortholog assessment: XIAP E3-dependent RIPK2 ubiquitination and NOD1/NOD2 signaling are independently established major molecular roles of this gene (PMIDs:22607974,29452636). Retain this immune-pathway claim on its own biological merits, alongside caspase inhibition; the scope of an apoptosis module does not make immune function non-core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:29452636 we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP acts directly in NOD2 signaling through RIPK2 ubiquitination. Reason: Mouse ortholog assessment: XIAP E3-dependent RIPK2 ubiquitination and NOD1/NOD2 signaling are independently established major molecular roles of this gene (PMIDs:22607974,29452636). Retain this immune-pathway claim on its own biological merits, alongside caspase inhibition; the scope of an apoptosis module does not make immune function non-core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:22607974 We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. PMID:29452636 we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. PMID:30026309 RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. |
| GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: XIAP acts directly in NOD2 signaling through RIPK2 ubiquitination. Reason: Mouse ortholog assessment: XIAP E3-dependent RIPK2 ubiquitination and NOD1/NOD2 signaling are independently established major molecular roles of this gene (PMIDs:22607974,29452636). Retain this immune-pathway claim on its own biological merits, alongside caspase inhibition; the scope of an apoptosis module does not make immune function non-core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:22607974 We find that XIAP ubiquitylates RIPK2 and recruits the linear ubiquitin chain assembly complex (LUBAC) to NOD2. PMID:29452636 we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. PMID:30026309 RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. |
| GO:0070534 protein K63-linked ubiquitination | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP mediates K63-linked ubiquitination of RIPK2 in NOD signaling. Reason: Mouse ortholog assessment: XIAP E3-dependent RIPK2 ubiquitination and NOD1/NOD2 signaling are independently established major molecular roles of this gene (PMIDs:22607974,29452636). Retain this immune-pathway claim on its own biological merits, alongside caspase inhibition; the scope of an apoptosis module does not make immune function non-core. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:29452636 we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Reason: Mouse ortholog assessment: XIAP directly monoubiquitinates Groucho/TLE corepressors and promotes their exchange for beta-catenin at TCF/Lef. This mechanistically supported Wnt role is retained alongside the other E3 outputs, independently of the apoptosis-module scope (PMID:22304967). Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:22304967 Upon Wnt pathway activation, XIAP is recruited to TCF/Lef where it monoubiquitylates Groucho (Gro)/TLE. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. Reason: Mouse ortholog assessment: XIAP directly monoubiquitinates Groucho/TLE corepressors and promotes their exchange for beta-catenin at TCF/Lef. This mechanistically supported Wnt role is retained alongside the other E3 outputs, independently of the apoptosis-module scope (PMID:22304967). Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:22304967 Upon Wnt pathway activation, XIAP is recruited to TCF/Lef where it monoubiquitylates Groucho (Gro)/TLE. |
| GO:0097110 scaffold protein binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: XIAP associates with scaffold partners in signaling assemblies. Reason: Curated mouse UniProt SUBUNIT statements include TAB1/MAP3K7IP1 and modulation of that association by DIABLO; human TAK1 signaling experiments independently support the pathway context. Retain the specific scaffold-binding inference without assigning TAB1 scaffolding or TAK1 kinase catalysis to XIAP. Supporting Evidence: |
| GO:0097179 protease inhibitor complex | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP forms a protease-inhibitor complex with caspase-7. Reason: Mouse ortholog assessment: The caspase-7 structural study directly supports XIAP in a caspase-inhibitory complex, the physical state underlying its apoptotic caspase inhibitor activity. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:11257230 Here we present the crystal structure of caspase-7 in complex with a potent inhibitory fragment from XIAP |
| GO:0097179 protease inhibitor complex | ISO GO_REF:0000119 | ACCEPT | Summary: XIAP forms a protease-inhibitor complex with caspase-7. Reason: Mouse ortholog assessment: The caspase-7 structural study directly supports XIAP in a caspase-inhibitory complex, the physical state underlying its apoptotic caspase inhibitor activity. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. Supporting Evidence: PMID:11257230 Here we present the crystal structure of caspase-7 in complex with a potent inhibitory fragment from XIAP |
| GO:0120283 protein serine/threonine kinase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: XIAP binds MAP3K7/TAK1 in a non-core JNK/NF-kappaB signaling branch. Reason: Mouse ortholog assessment: Protein serine/threonine kinase binding is more specific than generic protein binding and reflects the TAK1/JNK arm of XIAP signaling. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:0120283 protein serine/threonine kinase binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: XIAP binds MAP3K7/TAK1 in a non-core JNK/NF-kappaB signaling branch. Reason: Mouse ortholog assessment: Protein serine/threonine kinase binding is more specific than generic protein binding and reflects the TAK1/JNK arm of XIAP signaling. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:1902530 positive regulation of protein linear polyubiquitination | IEA GO_REF:0000107 | ACCEPT | Summary: XIAP recruits LUBAC to promote linear ubiquitination. Reason: Mouse ortholog assessment: The source series supports a distinction between XIAP E3 activity and positive control of HOIP/LUBAC-mediated linear-chain formation. PMID:21931591 reports stronger cIAP1 effects and weaker XIAP effects in its particular assays, which does not negate the XIAP-LUBAC recruitment mechanism established in PMID:22607974. Both rows judge the same supported process; neither attributes direct linear-chain catalysis to XIAP. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
| GO:1902530 positive regulation of protein linear polyubiquitination | ISS GO_REF:0000024 | ACCEPT | Summary: XIAP recruits LUBAC to promote linear ubiquitination. Reason: Mouse ortholog assessment: The source series supports a distinction between XIAP E3 activity and positive control of HOIP/LUBAC-mediated linear-chain formation. PMID:21931591 reports stronger cIAP1 effects and weaker XIAP effects in its particular assays, which does not negate the XIAP-LUBAC recruitment mechanism established in PMID:22607974. Both rows judge the same supported process; neither attributes direct linear-chain catalysis to XIAP. Human biochemical observations support the conserved XIAP mechanism; this row remains an orthology/phylogenetic inference rather than a newly claimed direct mouse assay. |
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