id: O15553
gene_symbol: MEFV
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MEFV encodes pyrin (also called marenostrin or TRIM20), a cytosolic
  innate-immune protein expressed predominantly in myeloid/granulocytic cells.
  Pyrin has an N-terminal PYRIN (PYD/DAPIN) domain, a central B-box-type zinc
  finger and coiled-coil region, and a C-terminal B30.2/SPRY (PRY-SPRY) domain;
  it belongs to the tripartite-motif (TRIM) family (TRIM20). Pyrin functions as
  an inflammasome sensor that detects pathogen-driven inactivation of the small
  GTPase RhoA. In the resting state, RhoA-activated kinases PKN1/PKN2
  phosphorylate pyrin (Ser208/Ser242), creating docking sites for inhibitory
  14-3-3 proteins that keep pyrin inactive. Loss of RhoA activity (e.g. by
  bacterial toxins/effectors) dephosphorylates pyrin, releases 14-3-3, and
  triggers assembly of the pyrin inflammasome: pyrin nucleates PYCARD/ASC speck
  (pyroptosome) formation through PYD-PYD interactions, activating caspase-1 and
  driving maturation of IL-1beta and IL-18 and pyroptotic cell death. Pyrin
  inflammasome activation in wild-type cells requires intact microtubules.
  Beyond this sensor role, pyrin also acts as a selective-autophagy receptor
  ("precision autophagy"): it serves as a platform that recruits ULK1,
  Beclin-1/BECN1, ATG16L1 and ATG8/LC3-family proteins to target inflammasome
  components (NLRP3, NLRP1, pro-caspase-1) for autophagic degradation, thereby
  restraining excessive IL-1beta/IL-18-driven inflammation. Pyrin localizes to
  the cytoplasm and cytoskeleton, associating with microtubules and actin
  filaments (perinuclear filaments, leading-edge ruffles/lamellipodia) and with
  ASC specks and autophagosomes; an alternatively spliced isoform lacking exon 2
  translocates to the nucleus. Gain-of-function MEFV mutations, mostly in the
  B30.2/SPRY domain, cause autosomal-recessive Familial Mediterranean Fever
  (FMF), and mutations affecting the Ser242 14-3-3 site cause autosomal-dominant
  Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND).
alternative_products:
- name: 1 (FL)
  id: O15553-2
- name: 2 (D2)
  id: O15553-1
  sequence_note: VSP_008223
- name: '3'
  id: O15553-3
  sequence_note: VSP_008223, VSP_047663
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of cytoplasmic localization, the correct primary compartment where pyrin acts.
    action: ACCEPT
    reason: Pyrin is a cytosolic protein and acts in the cytoplasm; consistent with experimental EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cytoskeleton'
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of involvement in innate immunity; correct high-level process for pyrin as an inflammasome sensor.
    action: ACCEPT
    reason: Pyrin is a central innate-immune inflammasome sensor; the broad term is correct, with more specific processes (pyroptosis, IL-1beta production) captured by other annotations.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Involved in the regulation of innate immunity and the inflammatory response
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) inference of a generic role in regulation of gene expression, propagated across the TRIM family. Pyrin acts post-translationally (inflammasome assembly, selective autophagy), not as a characterized regulator of gene expression.
    action: MARK_AS_OVER_ANNOTATED
    reason: This generic term is a TRIM-family phylogenetic over-propagation; there is no specific experimental evidence that pyrin regulates gene expression. Its characterized roles are post-translational (caspase-1 activation, autophagic degradation of inflammasome components).
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) inference of ubiquitin protein ligase activity propagated from the TRIM/RING family. Pyrin is classed as TRIM20 but lacks a canonical functional RING domain, and its characterized functions (inflammasome assembly, selective-autophagy receptor) do not depend on intrinsic E3 ligase activity.
    action: REMOVE
    reason: The fetched GOA line shows this is an IBA propagated through PANTHER:PTN007774218. OpenScientist resolved the prior uncertainty and found that MEFV lacks the RING catalytic domain required for canonical TRIM E3 ligase activity, has only a B-box zinc finger plus PYD/coiled-coil/B30.2-SPRY architecture, and has no direct experimental support for intrinsic ubiquitin ligase activity. This is a domain-loss/function-divergence over-propagation from RING-containing TRIM paralogs, so the annotation should be removed rather than merely marked over-annotated.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - PSEUDO_OR_SUBACTIVITY_LOSS
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN007774218
        source_label: PAINT TRIM ubiquitin ligase source node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: The fetched GOA line propagates GO:0061630 through this PANTHER
          source node, but MEFV/TRIM20 lacks the RING catalytic domain that
          supports ubiquitin protein ligase activity in canonical TRIM paralogs.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-goa.tsv
      supporting_text: "UniProtKB\tO15553\tMEFV\tenables\tGO:0061630\tubiquitin protein ligase activity\tmolecular_function\tECO:0000318\tIBA\tGO_REF:0000033\tMGI:MGI:2137355|MGI:MGI:2385051|MGI:MGI:2447992|MGI:MGI:2684862|MGI:MGI:2684869|MGI:MGI:3612190|PANTHER:PTN007774218|UniProtKB:P14373|UniProtKB:P19474|UniProtKB:Q12899|UniProtKB:Q86WT6|UniProtKB:Q8IWZ4|UniProtKB:Q8IYM9|UniProtKB:Q8WV44|UniProtKB:Q969Q1|UniProtKB:Q96A61|UniProtKB:Q9BVG3|UniProtKB:Q9BYV6|UniProtKB:Q9BZY9|UniProtKB:Q9C029|UniProtKB:Q9C030|UniProtKB:Q9H2S5\t9606\tHomo sapiens\tGO_Central\tPyrin\t20250903"
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: FT   ZN_FING         370..412
    - reference_id: file:human/MEFV/MEFV-hypotheses/function-hypothesis-go-0061630/openscientist.md
      supporting_text: The annotation of MEFV/TRIM20/pyrin with GO:0061630 (ubiquitin protein ligase activity) is a phylogenetic over-annotation that should be removed.
    - reference_id: file:human/MEFV/MEFV-hypotheses/function-hypothesis-go-0061630/openscientist.md
      supporting_text: Critically, no RING finger domain is annotated by UniProt, InterPro (IPR050143), Pfam, SMART, or PROSITE.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of cytosolic localization, the primary compartment where the pyrin inflammasome assembles.
    action: ACCEPT
    reason: Correct primary site of action; pyrin nucleates the ASC pyroptosome in the cytosol. Consistent with Reactome TAS and experimental evidence.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation
- term:
    id: GO:0001726
    label: ruffle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ruffle localization from the UniProt subcellular location; experimentally supported (pyrin polarizes to leading-edge ruffles in migrating monocytes, colocalizing with polymerizing actin).
    action: KEEP_AS_NON_CORE
    reason: Real but secondary cytoskeleton-associated localization reflecting actin association in migrating cells, not the core cytosolic inflammasome-assembly site.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Cell projection, ruffle {ECO:0000269|PubMed:11468188}
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of nuclear localization from UniProt; experimentally this reflects an alternatively spliced isoform (lacking exon 2) that translocates to the nucleus.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but isoform-specific (isoform 2 / lacking exon 2) and not the compartment of pyrin's core cytosolic inflammasome function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 2]: Nucleus {ECO:0000269|PubMed:11115844}'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from UniProt; the correct primary compartment, redundant with experimental EXP/IDA annotations.
    action: ACCEPT
    reason: Correct primary localization; pyrin acts in the cytoplasm.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10666224, ECO:0000269|PubMed:11498534
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of autophagosome localization from UniProt; experimentally supported by the precision-autophagy study where pyrin/TRIM20 localizes to autophagic structures while degrading inflammasome components.
    action: KEEP_AS_NON_CORE
    reason: Real localization tied to pyrin's selective-autophagy receptor role (a regulatory/secondary function), not its core cytosolic inflammasome assembly.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:26347139}
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoskeleton localization; experimentally pyrin associates with microtubules and actin filaments.
    action: KEEP_AS_NON_CORE
    reason: Real cytoskeletal association (microtubules/actin); microtubules are required for WT pyrin inflammasome activation, but the cytoskeleton itself is a supporting localization rather than the core inflammasome site.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cytoskeleton'
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of zinc ion binding, consistent with pyrin's B-box-type zinc finger.
    action: KEEP_AS_NON_CORE
    reason: Pyrin contains a B-box zinc finger that binds zinc structurally; correct but a structural/accessory property rather than the core inflammasome-sensing function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: ZN_FING          370..412
- term:
    id: GO:0030027
    label: lamellipodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of lamellipodium localization from UniProt; experimentally pyrin localizes to peripheral lamellar ruffles/lamellipodia via actin association.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary actin-associated localization in migrating cells, not the core cytosolic inflammasome site.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Cell projection, lamellipodium {ECO:0000269|PubMed:11468188}
- term:
    id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of positive regulation of IL-1beta production; corroborated experimentally (pyrin inflammasome drives IL-1beta maturation).
    action: ACCEPT
    reason: Correct core process; the pyrin inflammasome activates caspase-1 to produce mature IL-1beta. Redundant with the experimental IDA annotation (PMID:16037825).
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production
- term:
    id: GO:0050727
    label: regulation of inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of the generic parent term regulation of inflammatory response.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific positive and negative regulation of IL-1beta production and inflammatory-response terms better capture pyrin's role.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Involved in the regulation of innate immunity and the inflammatory response
- term:
    id: GO:0051707
    label: response to other organism
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of response to other organism; consistent with pyrin sensing pathogen-driven RhoA inactivation during bacterial infection.
    action: KEEP_AS_NON_CORE
    reason: Biologically reasonable (pyrin is a sensor of bacterial toxin/effector activity) but a broad term; the inflammasome/pyroptosis annotations capture the specific defense mechanism.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an integral part of host defense against pathogens, in response to bacterial infection
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11498534
  qualifier: enables
  review:
    summary: IPI interaction with PYCARD/ASC (Q9ULZ3), a functionally central interaction (PYD-PYD) for inflammasome assembly. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally important interaction (pyrin-ASC) but the bare protein binding term is uninformative per curation guidelines; the inflammasome/pyroptosome assembly annotations capture the functional consequence.
    supported_by:
    - reference_id: PMID:11498534
      supporting_text: Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16785446
  qualifier: enables
  review:
    summary: IPI interaction with CASP1/caspase-1 (P29466) via the B30.2 domain, modulating IL-1beta production. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with caspase-1 relevant to IL-1beta production, but the bare term is uninformative; the IL-1beta-production process annotations capture the function.
    supported_by:
    - reference_id: PMID:16785446
      supporting_text: The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17964261
  qualifier: enables
  review:
    summary: IPI interactions with PSTPIP1 (O43586) and ASC (Q9ULZ3); autoinflammatory PSTPIP1 mutants engage pyrin to activate the ASC pyroptosome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally relevant interactions (PSTPIP1, ASC) but the bare term is uninformative; pyroptosome assembly annotations capture the function.
    supported_by:
    - reference_id: PMID:17964261
      supporting_text: Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25006247
  qualifier: enables
  review:
    summary: IPI interaction with ASC (Q9ULZ3); structural study of pyrin-ASC PYD binding modes relevant to inflammasome assembly. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally central pyrin-ASC interaction but the bare term is uninformative; inflammasome assembly annotations capture the function.
    supported_by:
    - reference_id: PMID:25006247
      supporting_text: Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17964261
  qualifier: enables
  review:
    summary: IPI self-interaction (O15553-O15553); pyrin forms a homotrimer/oligomer, which is relevant to inflammasome nucleation.
    action: KEEP_AS_NON_CORE
    reason: Pyrin self-association (homotrimer) is real and relevant to oligomerization/inflammasome nucleation, but the term is descriptive rather than the core sensing function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Homotrimer
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22829933
  qualifier: enables
  review:
    summary: IPI self-interaction (O15553-O15553) reported in a study primarily on TRIM27/NOD2; supports pyrin self-association.
    action: KEEP_AS_NON_CORE
    reason: Records pyrin self-association consistent with its homotrimeric/oligomeric state; descriptive rather than the core function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Homotrimer
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25006247
  qualifier: enables
  review:
    summary: IPI self-interaction (O15553-O15553) from the structural study of pyrin PYD; supports pyrin self-association/oligomerization.
    action: KEEP_AS_NON_CORE
    reason: Pyrin self-association is real and relevant to oligomerization; descriptive rather than core sensing function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Homotrimer
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence-based plasma membrane localization. Pyrin is predominantly cytosolic/cytoskeletal; plasma-membrane staining likely reflects cortical actin association at ruffles/lamellipodia.
    action: KEEP_AS_NON_CORE
    reason: Not the established core compartment; pyrin is cytosolic. Membrane-proximal signal is plausibly explained by its cortical actin/leading-edge association, so retained as a non-core localization rather than removed.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: strongly polarized at the leading edge of the cell where it colocalizes with polymerizing actin
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:10666224
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization of pyrin in hematopoietic cells. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization where pyrin functions.
    supported_by:
    - reference_id: PMID:10666224
      supporting_text: subcellular localization of its corresponding protein, pyrin
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:11498534
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization of pyrin. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10666224, ECO:0000269|PubMed:11498534
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18577712
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization of pyrin (caspase-1 cleavage / NF-kB study). Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: ECO:0000269|PubMed:18577712
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:19584923
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization of pyrin (PSTPIP1 distribution study). Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: PMID:19584923
      supporting_text: Pyrin Modulates the Intracellular Distribution of PSTPIP1
- term:
    id: GO:0002221
    label: pattern recognition receptor signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:29196474
  qualifier: involved_in
  review:
    summary: ComplexPortal author-statement that pyrin participates in pattern-recognition-receptor (inflammasome) signaling. Pyrin is an inflammasome sensor that responds to perturbation of host RhoA, consistent with this term.
    action: ACCEPT
    reason: Pyrin functions as a sensor in inflammasome (PRR-type) signaling, nucleating ASC and activating caspase-1. Core process.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: NAS
  original_reference_id: PMID:27911804
  qualifier: located_in
  review:
    summary: Author-statement microtubule localization; microtubules are obligatorily required for WT pyrin inflammasome activation, and FMF mutations lift this requirement.
    action: KEEP_AS_NON_CORE
    reason: Microtubule association is functionally important for pyrin inflammasome activation in WT cells, but the microtubule is a supporting localization rather than pyrin's intrinsic site of action.
    supported_by:
    - reference_id: PMID:27911804
      supporting_text: Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation
- term:
    id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  evidence_type: IDA
  original_reference_id: PMID:16037825
  qualifier: involved_in
  review:
    summary: Direct evidence that pyrin activates caspase-1 via ASC oligomerization, driving IL-1beta production. Core process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; the pyrin inflammasome positively drives IL-1beta maturation through caspase-1.
    supported_by:
    - reference_id: PMID:16037825
      supporting_text: Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization
- term:
    id: GO:0061702
    label: canonical inflammasome complex
  evidence_type: IPI
  original_reference_id: PMID:16037825
  qualifier: part_of
  review:
    summary: Evidence that pyrin is part of an inflammasome complex (pyrin/ASC/caspase-1). Core cellular component for the sensor.
    action: ACCEPT
    reason: Core cellular component; pyrin is the sensor scaffold of the pyrin inflammasome, recruiting ASC and caspase-1.
    supported_by:
    - reference_id: PMID:16037825
      supporting_text: Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization
- term:
    id: GO:0070269
    label: pyroptotic inflammatory response
  evidence_type: NAS
  original_reference_id: PMID:29196474
  qualifier: involved_in
  review:
    summary: Author-statement that pyrin participates in pyroptotic inflammatory response; consistent with pyrin inflammasome-driven caspase-1 activation and pyroptosis.
    action: ACCEPT
    reason: Core process; the pyrin inflammasome triggers caspase-1-dependent pyroptosis.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27030597
  qualifier: enables
  review:
    summary: IPI interactions with 14-3-3 proteins (P27348, P31946, P61981, P62258, P63104, Q04917); 14-3-3 binds phosphorylated pyrin to hold it inactive, a key regulatory interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important inhibitory 14-3-3 interaction underlying pyrin phosphoregulation, but the bare term is uninformative; the regulatory mechanism is captured by the regulation-of-IL-1beta and pyroptosome-assembly annotations.
    supported_by:
    - reference_id: PMID:27030597
      supporting_text: Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
- term:
    id: GO:0032651
    label: regulation of interleukin-1 beta production
  evidence_type: IMP
  original_reference_id: PMID:27030597
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that pyrin activation (released from 14-3-3 inhibition) regulates IL-1beta production; PAAND/FMF mutations dysregulate this. Core process.
    action: ACCEPT
    reason: Core biological process with IMP support; pyrin controls IL-1beta production through its inflammasome, gated by PKN/14-3-3 phosphoregulation.
    supported_by:
    - reference_id: PMID:27030597
      supporting_text: a regulatory mechanism of pyrin activation
- term:
    id: GO:1904270
    label: pyroptosome complex assembly
  evidence_type: IDA
  original_reference_id: PMID:27030597
  qualifier: involved_in
  review:
    summary: Direct evidence that activated pyrin drives assembly of the ASC pyroptosome (speck). Core process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; pyrin nucleates ASC pyroptosome/speck assembly, the central event of pyrin inflammasome activation.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an innate immune sensor that triggers PYCARD/ASC specks formation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26347139
  qualifier: enables
  review:
    summary: IPI interactions with autophagy machinery and cargo (e.g. BECN1/O95166, ATG family members, GABARAP/Q9H0R8, MAP1LC3B/Q9GZQ8 partners) from the precision-autophagy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions underlying pyrin's selective-autophagy receptor role (assembling ULK1/Beclin-1/ATG16L1/ATG8), but the bare term is uninformative; the positive-regulation-of-autophagy and negative-regulation annotations capture the function.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:26347139
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization of pyrin/TRIM20 in the precision-autophagy study. Core compartment.
    action: ACCEPT
    reason: Direct experimental support for the primary cytoplasmic localization.
    supported_by:
    - reference_id: PMID:26347139
      supporting_text: TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IDA
  original_reference_id: PMID:26347139
  qualifier: involved_in
  review:
    summary: Direct evidence that pyrin/TRIM20 promotes (selective/precision) autophagy by assembling autophagy machinery and targeting inflammasome components for degradation.
    action: KEEP_AS_NON_CORE
    reason: Real and well-supported, but represents pyrin's secondary regulatory arm (selective-autophagy receptor) rather than its core inflammasome-sensor function. More precisely captured as selective autophagy/receptor activity than generic positive regulation of autophagy.
    supported_by:
    - reference_id: PMID:26347139
      supporting_text: TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation
- term:
    id: GO:0034341
    label: response to type II interferon
  evidence_type: IDA
  original_reference_id: PMID:26347139
  qualifier: involved_in
  review:
    summary: Direct evidence linking pyrin/TRIM20 to IFN-gamma-induced (precision) autophagy; TRIM20 is among the TRIMs required for IFN-gamma-induced autophagy.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary; reflects IFN-gamma-driven autophagy context rather than pyrin's core inflammasome-sensing function.
    supported_by:
    - reference_id: PMID:26347139
      supporting_text: All six TRIMs that were positive hits from the screen, TRIM1, TRIM8, TRIM20, TRIM21, TRIM22, and TRIM65 ... were required for
- term:
    id: GO:1900016
    label: negative regulation of cytokine production involved in inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:26347139
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that pyrin/TRIM20-mediated precision autophagy of inflammasome components limits inflammatory cytokine (IL-1beta/IL-18) production.
    action: KEEP_AS_NON_CORE
    reason: Real anti-inflammatory regulatory role via autophagic degradation of inflammasome components, but secondary to pyrin's core sensor function (which is pro-inflammatory).
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: hence preventing excessive IL1B- and IL18-mediated inflammation
- term:
    id: GO:1900226
    label: negative regulation of NLRP3 inflammasome complex assembly
  evidence_type: IMP
  original_reference_id: PMID:26347139
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that pyrin/TRIM20 negatively regulates NLRP3 inflammasome assembly by targeting NLRP3 (and NLRP1, pro-caspase-1) for autophagic degradation.
    action: KEEP_AS_NON_CORE
    reason: Real cross-regulatory function (pyrin restrains the distinct NLRP3 inflammasome via autophagy), but secondary to pyrin's own inflammasome-sensor role.
    supported_by:
    - reference_id: PMID:26347139
      supporting_text: TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: IPI interactions with autophagy proteins (BECN1/O95166, GABARAP/Q9H492) from a study showing TRIMs regulate autophagy and recognize substrates directly. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions supporting pyrin's selective-autophagy receptor function, but the bare term is uninformative.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-877361
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (Pyrin binds ASC). Consistent with the core cytosolic site of inflammasome assembly.
    action: ACCEPT
    reason: Correct cytosolic localization where pyrin nucleates the ASC inflammasome.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: an innate immune sensor that triggers PYCARD/ASC specks formation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-879221
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (PSTPIP1 binds Pyrin). Consistent with the core cytosolic site of action.
    action: ACCEPT
    reason: Correct cytosolic localization for pyrin-PSTPIP1 interaction in the cytosol.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization
- term:
    id: GO:0032691
    label: negative regulation of interleukin-1 beta production
  evidence_type: IMP
  original_reference_id: PMID:20041150
  qualifier: involved_in
  review:
    summary: IMP from a clinical-genetics study correlating MEFV missense variants with IL-1beta levels in fibromyalgia. Supports a negative-regulatory role for pyrin on IL-1beta production.
    action: KEEP_AS_NON_CORE
    reason: Consistent with pyrin's anti-inflammatory (autophagy-mediated) arm, but derived from a disease-association study (fibromyalgia) and represents a secondary regulatory effect rather than the core sensor function.
    supported_by:
    - reference_id: PMID:20041150
      supporting_text: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels
- term:
    id: GO:0032695
    label: negative regulation of interleukin-12 production
  evidence_type: IMP
  original_reference_id: PMID:20041150
  qualifier: involved_in
  review:
    summary: IMP from the same fibromyalgia/MEFV clinical-genetics study; negative regulation of IL-12 production.
    action: KEEP_AS_NON_CORE
    reason: Peripheral cytokine-regulatory effect from a disease-association study; not pyrin's core function and weakly specific.
    supported_by:
    - reference_id: PMID:20041150
      supporting_text: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:16403826
  qualifier: involved_in
  review:
    summary: IMP from a clinical study of FMF patients and MEFV-mutation carriers showing subclinical inflammation, supporting a normally anti-inflammatory (restraining) role for pyrin.
    action: KEEP_AS_NON_CORE
    reason: Reflects pyrin's anti-inflammatory regulatory arm (loss-of-function leads to inflammation); a secondary regulatory role rather than the core sensor function, and derived from clinical inflammation phenotyping.
    supported_by:
    - reference_id: PMID:16403826
      supporting_text: Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations
- term:
    id: GO:0071641
    label: negative regulation of macrophage inflammatory protein 1 alpha production
  evidence_type: IMP
  original_reference_id: PMID:20041150
  qualifier: involved_in
  review:
    summary: IMP from the fibromyalgia/MEFV study; negative regulation of MIP-1alpha (CCL3) production.
    action: KEEP_AS_NON_CORE
    reason: Highly specific peripheral cytokine-regulatory effect from a disease-association study; not a core pyrin function.
    supported_by:
    - reference_id: PMID:20041150
      supporting_text: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IDA
  original_reference_id: PMID:11468188
  qualifier: enables
  review:
    summary: Direct evidence that pyrin associates with actin filaments and colocalizes with polymerizing actin at ruffles/lamellipodia.
    action: KEEP_AS_NON_CORE
    reason: Real cytoskeletal association (actin/microtubules), relevant to pyrin localization and possibly to inflammasome regulation, but not the core inflammasome-sensing molecular function.
    supported_by:
    - reference_id: PMID:11468188
      supporting_text: The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11115844
  qualifier: located_in
  review:
    summary: Direct evidence that an alternatively spliced pyrin isoform (lacking exon 2) translocates to the nucleus.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but isoform-specific and not the compartment of pyrin's core cytosolic inflammasome function.
    supported_by:
    - reference_id: PMID:11115844
      supporting_text: Alternative splicing at the MEFV locus ... regulates translocation of the marenostrin/pyrin protein to the nucleus
- term:
    id: GO:0005875
    label: microtubule associated complex
  evidence_type: IDA
  original_reference_id: PMID:11468188
  qualifier: part_of
  review:
    summary: Direct evidence that pyrin associates with microtubules. Microtubule integrity is required for WT pyrin inflammasome activation.
    action: KEEP_AS_NON_CORE
    reason: Functionally relevant microtubule association (required for inflammasome activation in WT cells), but a supporting localization/component rather than pyrin's core inflammasome assembly.
    supported_by:
    - reference_id: PMID:11468188
      supporting_text: pyrin, associates with microtubules and colocalizes with actin filaments
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:11468188
  qualifier: involved_in
  review:
    summary: Direct evidence implicating pyrin in the inflammatory response (colocalizes with ASC in inflammasome specks).
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent process; the specific inflammasome/pyroptosis/IL-1beta-production annotations capture pyrin's role more precisely.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: In pre-apoptotic cells, colocalizes with PYCARD/ASC in large specks (inflammasomes)
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: NAS
  original_reference_id: PMID:11115844
  qualifier: enables
  review:
    summary: Author-statement zinc ion binding, consistent with pyrin's B-box zinc finger.
    action: KEEP_AS_NON_CORE
    reason: Pyrin's B-box binds zinc structurally; a structural/accessory property rather than the core inflammasome-sensing function. Redundant with the InterPro IEA zinc-binding annotation.
    supported_by:
    - reference_id: file:human/MEFV/MEFV-uniprot.txt
      supporting_text: ZN_FING          370..412
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: file:human/MEFV/MEFV-goa.tsv
  title: GOA annotations for human MEFV
  findings:
  - statement: The fetched GOA line for the contested GO:0061630 IBA annotation
      propagates ubiquitin protein ligase activity through PANTHER:PTN007774218
      and a broad TRIM-family source set.
    supporting_text: "UniProtKB\tO15553\tMEFV\tenables\tGO:0061630\tubiquitin protein ligase activity\tmolecular_function\tECO:0000318\tIBA\tGO_REF:0000033\tMGI:MGI:2137355|MGI:MGI:2385051|MGI:MGI:2447992|MGI:MGI:2684862|MGI:MGI:2684869|MGI:MGI:3612190|PANTHER:PTN007774218|UniProtKB:P14373|UniProtKB:P19474|UniProtKB:Q12899|UniProtKB:Q86WT6|UniProtKB:Q8IWZ4|UniProtKB:Q8IYM9|UniProtKB:Q8WV44|UniProtKB:Q969Q1|UniProtKB:Q96A61|UniProtKB:Q9BVG3|UniProtKB:Q9BYV6|UniProtKB:Q9BZY9|UniProtKB:Q9C029|UniProtKB:Q9C030|UniProtKB:Q9H2S5\t9606\tHomo sapiens\tGO_Central\tPyrin\t20250903"
    reference_section_type: OTHER
- id: file:human/MEFV/MEFV-hypotheses/function-hypothesis-go-0061630/openscientist.md
  title: OpenScientist hypothesis investigation - MEFV ubiquitin protein ligase activity
  publication_type: DEEP_RESEARCH
  findings:
  - statement: OpenScientist found that the GO:0061630 IBA assignment is a phylogenetic
      over-annotation and recommended removal.
    supporting_text: The annotation of MEFV/TRIM20/pyrin with GO:0061630 (ubiquitin protein ligase activity) is a phylogenetic over-annotation that should be removed.
    reference_section_type: OTHER
  - statement: OpenScientist found no annotated RING domain in MEFV across the major
      domain resources checked.
    supporting_text: Critically, no RING finger domain is annotated by UniProt, InterPro (IPR050143), Pfam, SMART, or PROSITE.
    reference_section_type: OTHER
  - statement: OpenScientist identified the supported MEFV functions as autophagy
      receptor activity and inflammasome sensing rather than E3 ubiquitin ligase
      activity.
    supporting_text: MEFV's primary documented functions are autophagy receptor activity and inflammasome sensing
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: OpenScientist autonomous-compute report directly evaluates the
      contested GO:0061630 IBA, includes domain/motif and AlphaFold provenance,
      and supports changing the previous over-annotation flag to removal while
      preserving the caveat that a direct negative ubiquitination assay has not
      been published.
- id: PMID:10666224
  title: Hematopoietic-specific expression of MEFV, the gene mutated in familial Mediterranean
    fever, and subcellular localization of its corresponding protein, pyrin.
  findings: []
- id: PMID:11115844
  title: Alternative splicing at the MEFV locus involved in familial Mediterranean
    fever regulates translocation of the marenostrin/pyrin protein to the nucleus.
  findings: []
- id: PMID:11468188
  title: The familial Mediterranean fever protein, pyrin, associates with microtubules
    and colocalizes with actin filaments.
  findings: []
- id: PMID:11498534
  title: Interaction between pyrin and the apoptotic speck protein (ASC) modulates
    ASC-induced apoptosis.
  findings: []
- id: PMID:16037825
  title: Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization.
  findings:
  - statement: Pyrin (like cryopyrin/NLRP3) activates caspase-1 via ASC oligomerization, driving IL-1beta production, without activating NF-kappaB.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the pro-inflammatory pyrin-ASC-caspase-1 axis (core sensor function). Abstract-only in cache.
- id: PMID:16403826
  title: Clinical and subclinical inflammation in patients with familial Mediterranean
    fever and in heterozygous carriers of MEFV mutations.
  findings: []
- id: PMID:16785446
  title: The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts
    directly with caspase-1 to modulate IL-1beta production.
  findings: []
- id: PMID:17964261
  title: Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory
    PSTPIP1 mutants.
  findings: []
- id: PMID:18577712
  title: The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1
    and activates NF-kappaB through its N-terminal fragment.
  findings: []
- id: PMID:19584923
  title: Pyrin Modulates the Intracellular Distribution of PSTPIP1.
  findings: []
- id: PMID:20041150
  title: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome
    and correlate with elevated IL-1beta plasma levels.
  findings: []
- id: PMID:22829933
  title: TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.
  findings: []
- id: PMID:25006247
  title: Identification of multifaceted binding modes for pyrin and ASC pyrin domains
    gives insights into pyrin inflammasome assembly.
  findings: []
- id: PMID:25127057
  title: TRIM proteins regulate autophagy and can target autophagic substrates by
    direct recognition.
  findings: []
- id: PMID:26347139
  title: TRIM-mediated precision autophagy targets cytoplasmic regulators of innate
    immunity.
  findings:
  - statement: Pyrin/TRIM20 is a selective-autophagy receptor that targets inflammasome components NLRP3, NLRP1 and pro-caspase-1 for autophagic degradation by assembling ULK1, Beclin-1, ATG16L1 and ATG8/LC3; FMF mutations impair this autophagic function.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Establishes pyrin's secondary anti-inflammatory selective-autophagy receptor (precision autophagy) role and links it to FMF mutations.
- id: PMID:27030597
  title: Familial autoinflammation with neutrophilic dermatosis reveals a regulatory
    mechanism of pyrin activation.
  findings:
  - statement: Pyrin activation is gated by PKN1/PKN2 phosphorylation (Ser208/Ser242) and inhibitory 14-3-3 binding; dephosphorylation releases 14-3-3 and triggers pyrin inflammasome assembly. PAAND-causing mutations at the Ser242 site cause constitutive activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines the PKN/14-3-3 phosphoregulatory switch controlling pyrin inflammasome activation and the PAAND disease mechanism. Abstract-only in cache (full_text_available false).
- id: PMID:27911804
  title: Familial Mediterranean fever mutations lift the obligatory requirement for
    microtubules in Pyrin inflammasome activation.
  findings:
  - statement: Wild-type pyrin inflammasome activation requires intact microtubules; FMF-associated mutations remove this microtubule dependence.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes microtubule dependence of WT pyrin inflammasome activation and its loss in FMF.
- id: PMID:29196474
  title: Inflammasome activation and assembly at a glance.
  findings: []
- id: Reactome:R-HSA-877361
  title: Pyrin binds ASC
  findings: []
- id: Reactome:R-HSA-879221
  title: PSTPIP1 binds Pyrin
  findings: []
core_functions:
- description: Acts as a cytosolic inflammasome sensor that detects pathogen-driven inactivation of RhoA (sensed via loss of PKN1/PKN2 phosphorylation and release of inhibitory 14-3-3), and nucleates assembly of the pyrin inflammasome by recruiting PYCARD/ASC into a pyroptosome/speck, thereby activating caspase-1 to drive IL-1beta/IL-18 maturation and pyroptosis.
  supported_by:
  - reference_id: PMID:16037825
    supporting_text: Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization
  - reference_id: PMID:27030597
    supporting_text: Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0002221
    label: pattern recognition receptor signaling pathway
  - id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  - id: GO:1904270
    label: pyroptosome complex assembly
  - id: GO:0070269
    label: pyroptotic inflammatory response
- description: Functions as a selective-autophagy (precision autophagy) receptor that serves as a platform assembling ULK1, Beclin-1/BECN1, ATG16L1 and ATG8/LC3-family proteins to target inflammasome components (NLRP3, NLRP1, pro-caspase-1) for autophagic degradation, restraining excessive IL-1beta/IL-18-driven inflammation.
  supported_by:
  - reference_id: PMID:26347139
    supporting_text: TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation
  locations:
  - id: GO:0005776
    label: autophagosome
  directly_involved_in:
  - id: GO:1900226
    label: negative regulation of NLRP3 inflammasome complex assembly
  - id: GO:1900016
    label: negative regulation of cytokine production involved in inflammatory response
suggested_questions:
- question: How is the balance between pyrin's pro-inflammatory inflammasome-sensor arm and its anti-inflammatory selective-autophagy receptor arm coordinated within the same cell, and is it stimulus- or compartment-dependent?
- question: Does human pyrin possess any intrinsic enzymatic (e.g. ubiquitin ligase) activity, or are all its functions scaffold/receptor-based given the lack of a canonical functional RING domain?
suggested_experiments:
- description: Reconstitute the pyrin inflammasome in vitro and in cells with phosphomimetic/phospho-dead Ser208/Ser242 variants and 14-3-3 depletion, measuring ASC speck formation and caspase-1 activation to map the RhoA-PKN-14-3-3 activation switch.
- description: Perform quantitative degradomics/ubiquitinomics in MEFV-knockout versus FMF-mutant macrophages under inflammasome-activating and autophagy-inducing conditions to define pyrin's autophagic substrate repertoire and test for any intrinsic E3 ligase activity.