CASP12

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: Q6UXS9
gene_symbol: CASP12
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: 1 (Epsilon {ECO:0000303|PubMed:12054529}, Gamma)
  id: Q6UXS9-1
- name: 2 (Alpha {ECO:0000303|PubMed:12054529}, Beta)
  id: Q6UXS9-2
  sequence_note: VSP_030954, VSP_030955
- name: 3 (Iota {ECO:0000303|PubMed:12054529})
  id: Q6UXS9-3
  sequence_note: VSP_061925, VSP_061927
- name: 4 (Zeta {ECO:0000303|PubMed:12054529}, Epsilon)
  id: Q6UXS9-4
  sequence_note: VSP_061929
- name: 5 (Eta {ECO:0000303|PubMed:12054529}, Delta)
  id: Q6UXS9-5
  sequence_note: VSP_061928
- name: 6 (Gamma {ECO:0000303|PubMed:12054529}, Zeta)
  id: Q6UXS9-6
  sequence_note: VSP_061926
- name: 7 (Theta {ECO:0000303|PubMed:12054529}, Eta)
  id: Q6UXS9-7
  sequence_note: VSP_061927
- name: 8 (Delta {ECO:0000303|PubMed:12054529}, Theta)
  id: Q6UXS9-8
  sequence_note: VSP_061925, VSP_061926
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'cytoplasm: a core subcellular location for CASP12.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'cytosol: a core subcellular location for CASP12.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0070269
    label: pyroptotic inflammatory response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Pyroptotic inflammatory response (IBA), propagated from active caspases. Pyroptosis requires
      catalytic gasdermin cleavage, which an inactive caspase cannot perform.
    action: MARK_AS_OVER_ANNOTATED
    reason: Phylogenetic over-propagation of a catalysis-dependent process onto an inactive pseudo-caspase;
      parallels the REMOVE of the upstream cysteine-type endopeptidase activity.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'apoptotic process: process annotation for CASP12.'
    action: KEEP_AS_NON_CORE
    reason: Valid but non-core / secondary.
- term:
    id: GO:0050729
    label: positive regulation of inflammatory response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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).
    action: REMOVE
    reason: Phylogenetic over-propagation of caspase activity onto an inactive pseudo-caspase; contradicted
      by the IKR NOT. Remove.
- term:
    id: GO:0072558
    label: NLRP1 inflammasome complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: 'NLRP1 inflammasome complex: a secondary/broad localization for CASP12.'
    action: KEEP_AS_NON_CORE
    reason: Plausible but non-core (broad term or context-specific).
- term:
    id: GO:0043525
    label: positive regulation of neuron apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'positive regulation of neuron apoptotic process: process annotation for CASP12.'
    action: KEEP_AS_NON_CORE
    reason: Valid but non-core / secondary.
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Proteolysis (IEA) inferred from the (absent) peptidase activity.
    action: REMOVE
    reason: Process annotation dependent on catalytic activity the protein lacks. Remove.
- term:
    id: GO:0008234
    label: cysteine-type peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive 'cysteine-type peptidase activity' (IEA), the parent of the NOT-ed caspase activity,
      from the peptidase C14A family signature.
    action: REMOVE
    reason: Electronic over-propagation of peptidase activity onto an inactive family member. Remove.
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: 'regulation of apoptotic process: process annotation for CASP12.'
    action: KEEP_AS_NON_CORE
    reason: Valid but non-core / secondary.
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IKR
  original_reference_id: PMID:12054529
  qualifier: enables
  negated: true
  review:
    summary: 'NOT: CASP12 does not have cysteine-type endopeptidase activity (IKR, inferred from key catalytic
      residues). Human caspase-12 is an inactive ''pseudo-caspase''.'
    action: ACCEPT
    reason: Correct negation based on key active-site residues. Retain.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10638761
  qualifier: located_in
  review:
    summary: 'endoplasmic reticulum: a core subcellular location for CASP12.'
    action: ACCEPT
    reason: Correct core localization.
references:
- id: GO_REF:0000002
  title: GO annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified annotations to orthologs by curator judgment
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: GO annotation based on curation of immunofluorescence data (HPA)
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Automatic GO annotation from UniProtKB-KW mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/CASP12/CASP12-uniprot.txt
  title: UniProt entry for CASP12
  findings: []
- id: PMID:10638761
  title: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.
  findings: []
- id: PMID:12054529
  title: Human caspase 12 has acquired deleterious mutations.
  findings: []
aliases:
- CASP-12
- Inactive caspase-12
core_functions:
- description: Catalytically inactive caspase (pseudo-caspase) that acts as a non-enzymatic, dominant-negative
    modulator of inflammatory-caspase / inflammasome (caspase-1) signaling rather than as a protease;
    localizes to the ER.
  molecular_function:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: file:human/CASP12/CASP12-uniprot.txt
    supporting_text: negative regulator of inflammatory
suggested_questions:
- question: Through what protein interactions does inactive CASP12 modulate caspase-1/inflammasome activity,
    and is the direction (positive vs negative regulation) context-dependent?
suggested_experiments:
- hypothesis: Full-length CASP12 dampens caspase-1 activation by competitive, non-catalytic binding.
  description: Reconstitute inflammasome activation with and without full-length vs truncated CASP12 and
    measure caspase-1 activity and IL-1B release.