Caspase-12 (CASP12) in humans is an inactive 'pseudo-caspase' of the peptidase C14A family. In the reference human genome a nonsense polymorphism truncates the protein, and even the rare full-length variant lacks key catalytic-site residues, so it has no cysteine-type endopeptidase activity. Rather than cleaving substrates, CASP12 acts as a dominant-negative modulator of inflammatory caspase / inflammasome signaling (dampening caspase-1-dependent responses), and has reported roles in ER-stress responses; the full-length allele is associated with altered sepsis susceptibility.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm: a core subcellular location for CASP12. Reason: Correct core localization. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: cytosol: a core subcellular location for CASP12. Reason: Correct core localization. |
| GO:0070269 pyroptotic inflammatory response | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Pyroptotic inflammatory response (IBA), propagated from active caspases. Pyroptosis requires catalytic gasdermin cleavage, which an inactive caspase cannot perform. Reason: Phylogenetic over-propagation of a catalysis-dependent process onto an inactive pseudo-caspase; parallels the REMOVE of the upstream cysteine-type endopeptidase activity. |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: apoptotic process: process annotation for CASP12. Reason: Valid but non-core / secondary. |
| GO:0050729 positive regulation of inflammatory response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positive regulation of inflammatory response (IBA), phylogenetically propagated from active inflammatory caspases. Human CASP12 is reported instead as a negative/dominant-negative modulator of caspase-1/inflammasome signaling, so the direction is uncertain for this inactive member. Reason: Direction of effect is debated for the inactive human protein; keep as non-core pending direct evidence rather than asserting it as a core pro-inflammatory function. |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | REMOVE | Summary: Positive cysteine-type endopeptidase activity (IBA) propagated phylogenetically from active caspases. CASP12 is catalytically inactive (it directly conflicts with the curated NOT for the same term). Reason: Phylogenetic over-propagation of caspase activity onto an inactive pseudo-caspase; contradicted by the IKR NOT. OpenScientist independently confirmed this as an over-annotated phylogenetic transfer from active caspases. Remove. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG PSEUDO OR SUBACTIVITY LOSS Sources checked: GO_REF:0000033 · PAINT phylogenetic IBA inference SUPPORTS SOURCE BUT NOT TARGET The family-level caspase inference captures active inflammatory caspases, but human CASP12 has lineage-specific catalytic loss and an existing IKR NOT annotation for this term. UniProtKB:P29466 · human CASP1 SUPPORTS SOURCE BUT NOT TARGET CASP1 is an active inflammatory caspase supporting cysteine-type endopeptidase activity; CASP12 is an inactive pseudo-caspase paralog. Supporting Evidence: file:human/CASP12/CASP12-hypotheses/function-hypothesis-go-0004197/openscientist.md The IBA annotation assigning cysteine-type endopeptidase activity (GO:0004197) to human CASP12 (Q6UXS9) is over-annotated and should be removed or superseded by the existing IKR (Inferred from Key Residues) negation. |
| GO:0072558 NLRP1 inflammasome complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NLRP1 inflammasome complex: a secondary/broad localization for CASP12. Reason: Plausible but non-core (broad term or context-specific). |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: positive regulation of neuron apoptotic process: process annotation for CASP12. Reason: Valid but non-core / secondary. |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | REMOVE | Summary: Proteolysis (IEA) inferred from the (absent) peptidase activity. Reason: Process annotation dependent on catalytic activity the protein lacks. Remove. |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000002 | REMOVE | Summary: Positive 'cysteine-type peptidase activity' (IEA), the parent of the NOT-ed caspase activity, from the peptidase C14A family signature. Reason: Electronic over-propagation of peptidase activity onto an inactive family member. Remove. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: regulation of apoptotic process: process annotation for CASP12. Reason: Valid but non-core / secondary. |
| GO:0004197 cysteine-type endopeptidase activity | IKR NOT PMID:12054529 Human caspase 12 has acquired deleterious mutations. | ACCEPT | Summary: NOT: CASP12 does not have cysteine-type endopeptidase activity (IKR, inferred from key catalytic residues). Human caspase-12 is an inactive 'pseudo-caspase'. Reason: Correct negation based on key active-site residues. Retain. Supporting Evidence: file:human/CASP12/CASP12-hypotheses/function-hypothesis-go-0004197/openscientist.md The existing IKR NOT|enables annotation correctly reflects the molecular biology and should be retained as the authoritative annotation. |
| GO:0005783 endoplasmic reticulum | IDA PMID:10638761 Caspase-12 mediates endoplasmic-reticulum-specific apoptosis... | ACCEPT | Summary: endoplasmic reticulum: a core subcellular location for CASP12. Reason: Correct core localization. |
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Download this section (compressed HTML)Q: Through what protein interactions does inactive CASP12 modulate caspase-1/inflammasome activity, and is the direction (positive vs negative regulation) context-dependent?
Experiment: Reconstitute inflammasome activation with and without full-length vs truncated CASP12 and measure caspase-1 activity and IL-1B release.
Hypothesis: Full-length CASP12 dampens caspase-1 activation by competitive, non-catalytic binding.
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