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). In addition to the established indirect route, in which RhoA inactivation by bacterial toxins removes PKN1/2-mediated phosphorylation of pyrin and releases inhibitory 14-3-3 proteins, the pyrin B30.2/SPRY domain binds the RHO-family GTPase CDC42 directly; this interaction controls pyrin localisation and the threshold for inflammasome assembly, so pyrin is regulated by two RHO-family GTPases through different mechanisms. Some pathogenic MEFV variants hyperactivate pyrin without requiring CDC42, indicating more than one activation pathway.
Definition: A protein complex nucleated by pyrin (MEFV) together with ASC/PYCARD and pro-caspase-1, which assembles in response to inactivation of RHO-family GTPase signalling and activates caspase-1, leading to IL-1beta and IL-18 maturation and to pyroptosis.
Justification: GO carries dedicated cellular-component terms for the NLRP1 (GO:0072558), NLRP3 (GO:0072559), NLRP6 (GO:0140738), CARD8 (GO:0140634), AIM2 (GO:0097169) and IPAF (GO:0072557) inflammasomes, but none for the pyrin inflammasome, although it is an equally well-established sensor-nucleated complex and the entity that MEFV variants dysregulate in familial Mediterranean fever. Without it, pyrin's own complex cannot be named and MEFV is left annotated only to regulation of other inflammasomes.
Parent term: canonical inflammasome complex
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cytoplasmic localization, the correct primary compartment where pyrin acts. Reason: Pyrin is a cytosolic protein and acts in the cytoplasm; consistent with experimental EXP/IDA evidence. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cytoskeleton |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of involvement in innate immunity; correct high-level process for pyrin as an inflammasome sensor. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Involved in the regulation of innate immunity and the inflammatory response |
| GO:0010468 regulation of gene expression | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. 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). |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | REMOVE | 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. 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 Sources checked: PANTHER:PTN007774218 · PAINT TRIM ubiquitin ligase source node SUPPORTS SOURCE BUT NOT TARGET 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. Supporting Evidence: file:human/MEFV/MEFV-goa.tsv UniProtKB O15553 MEFV enables GO:0061630 ubiquitin protein ligase activity molecular_function ECO:0000318 IBA GO_REF:0000033 MGI: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 9606 Homo sapiens GO_Central Pyrin 20250903 file:human/MEFV/MEFV-uniprot.txt Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members file:human/MEFV/MEFV-uniprot.txt FT ZN_FING 370..412 file:human/MEFV/MEFV-hypotheses/function-hypothesis-go-0061630/openscientist.md The annotation of MEFV/TRIM20/pyrin with GO:0061630 (ubiquitin protein ligase activity) is a phylogenetic over-annotation that should be removed. file:human/MEFV/MEFV-hypotheses/function-hypothesis-go-0061630/openscientist.md Critically, no RING finger domain is annotated by UniProt, InterPro (IPR050143), Pfam, SMART, or PROSITE. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cytosolic localization, the primary compartment where the pyrin inflammasome assembles. Reason: Correct primary site of action; pyrin nucleates the ASC pyroptosome in the cytosol. Consistent with Reactome TAS and experimental evidence. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation |
| GO:0001726 ruffle | IEA GO_REF:0000044 | KEEP AS NON CORE | 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). Reason: Real but secondary cytoskeleton-associated localization reflecting actin association in migrating cells, not the core cytosolic inflammasome-assembly site. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Cell projection, ruffle {ECO:0000269|PubMed:11468188} |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of nuclear localization from UniProt; experimentally this reflects an alternatively spliced isoform (lacking exon 2) that translocates to the nucleus. Reason: Nuclear localization is real but isoform-specific (isoform 2 / lacking exon 2) and not the compartment of pyrin's core cytosolic inflammasome function. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Nucleus {ECO:0000269|PubMed:11115844} |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from UniProt; the correct primary compartment, redundant with experimental EXP/IDA annotations. Reason: Correct primary localization; pyrin acts in the cytoplasm. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10666224, ECO:0000269|PubMed:11498534 |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Real localization tied to pyrin's selective-autophagy receptor role (a regulatory/secondary function), not its core cytosolic inflammasome assembly. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:26347139} |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of cytoskeleton localization; experimentally pyrin associates with microtubules and actin filaments. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm, cytoskeleton |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment of zinc ion binding, consistent with pyrin's B-box-type zinc finger. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt ZN_FING 370..412 |
| GO:0030027 lamellipodium | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of lamellipodium localization from UniProt; experimentally pyrin localizes to peripheral lamellar ruffles/lamellipodia via actin association. Reason: Real but secondary actin-associated localization in migrating cells, not the core cytosolic inflammasome site. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Cell projection, lamellipodium {ECO:0000269|PubMed:11468188} |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of positive regulation of IL-1beta production; corroborated experimentally (pyrin inflammasome drives IL-1beta maturation). Reason: Correct core process; the pyrin inflammasome activates caspase-1 to produce mature IL-1beta. Redundant with the experimental IDA annotation (PMID:16037825). Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production |
| GO:0050727 regulation of inflammatory response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of the generic parent term regulation of inflammatory response. Reason: Correct but generic; the specific positive and negative regulation of IL-1beta production and inflammatory-response terms better capture pyrin's role. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Involved in the regulation of innate immunity and the inflammatory response |
| GO:0051707 response to other organism | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of response to other organism; consistent with pyrin sensing pathogen-driven RhoA inactivation during bacterial infection. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an integral part of host defense against pathogens, in response to bacterial infection |
| GO:0005515 protein binding | IPI PMID:11498534 Interaction between pyrin and the apoptotic speck protein (A... | KEEP AS NON CORE | Summary: IPI interaction with PYCARD/ASC (Q9ULZ3), a functionally central interaction (PYD-PYD) for inflammasome assembly. Bare protein binding is uninformative. 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. Supporting Evidence: PMID:11498534 Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis |
| GO:0005515 protein binding | IPI PMID:16785446 The B30.2 domain of pyrin, the familial Mediterranean fever ... | KEEP AS NON CORE | Summary: IPI interaction with CASP1/caspase-1 (P29466) via the B30.2 domain, modulating IL-1beta production. Bare protein binding is uninformative. 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. Supporting Evidence: PMID:16785446 The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production |
| GO:0005515 protein binding | IPI PMID:17964261 Pyrin activates the ASC pyroptosome in response to engagemen... | KEEP AS NON CORE | Summary: IPI interactions with PSTPIP1 (O43586) and ASC (Q9ULZ3); autoinflammatory PSTPIP1 mutants engage pyrin to activate the ASC pyroptosome. Bare protein binding is uninformative. Reason: Records real, functionally relevant interactions (PSTPIP1, ASC) but the bare term is uninformative; pyroptosome assembly annotations capture the function. Supporting Evidence: PMID:17964261 Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants |
| GO:0005515 protein binding | IPI PMID:25006247 Identification of multifaceted binding modes for pyrin and A... | KEEP AS NON CORE | Summary: IPI interaction with ASC (Q9ULZ3); structural study of pyrin-ASC PYD binding modes relevant to inflammasome assembly. Bare protein binding is uninformative. Reason: Records a real, functionally central pyrin-ASC interaction but the bare term is uninformative; inflammasome assembly annotations capture the function. Supporting Evidence: PMID:25006247 Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly |
| GO:0042802 identical protein binding | IPI PMID:17964261 Pyrin activates the ASC pyroptosome in response to engagemen... | KEEP AS NON CORE | Summary: IPI self-interaction (O15553-O15553); pyrin forms a homotrimer/oligomer, which is relevant to inflammasome nucleation. Reason: Pyrin self-association (homotrimer) is real and relevant to oligomerization/inflammasome nucleation, but the term is descriptive rather than the core sensing function. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Homotrimer |
| GO:0042802 identical protein binding | IPI PMID:22829933 TRIM27 negatively regulates NOD2 by ubiquitination and prote... | KEEP AS NON CORE | Summary: IPI self-interaction (O15553-O15553) reported in a study primarily on TRIM27/NOD2; supports pyrin self-association. Reason: Records pyrin self-association consistent with its homotrimeric/oligomeric state; descriptive rather than the core function. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Homotrimer |
| GO:0042802 identical protein binding | IPI PMID:25006247 Identification of multifaceted binding modes for pyrin and A... | KEEP AS NON CORE | Summary: IPI self-interaction (O15553-O15553) from the structural study of pyrin PYD; supports pyrin self-association/oligomerization. Reason: Pyrin self-association is real and relevant to oligomerization; descriptive rather than core sensing function. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Homotrimer |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence-based plasma membrane localization. Pyrin is predominantly cytosolic/cytoskeletal; plasma-membrane staining likely reflects cortical actin association at ruffles/lamellipodia. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt strongly polarized at the leading edge of the cell where it colocalizes with polymerizing actin |
| GO:0005737 cytoplasm | EXP PMID:10666224 Hematopoietic-specific expression of MEFV, the gene mutated ... | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of pyrin in hematopoietic cells. Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization where pyrin functions. Supporting Evidence: PMID:10666224 subcellular localization of its corresponding protein, pyrin |
| GO:0005737 cytoplasm | EXP PMID:11498534 Interaction between pyrin and the apoptotic speck protein (A... | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of pyrin. Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Cytoplasm {ECO:0000269|PubMed:10666224, ECO:0000269|PubMed:11498534 |
| GO:0005737 cytoplasm | EXP PMID:18577712 The familial Mediterranean fever protein, pyrin, is cleaved ... | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of pyrin (caspase-1 cleavage / NF-kB study). Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt ECO:0000269|PubMed:18577712 |
| GO:0005737 cytoplasm | EXP PMID:19584923 Pyrin Modulates the Intracellular Distribution of PSTPIP1. | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of pyrin (PSTPIP1 distribution study). Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: PMID:19584923 Pyrin Modulates the Intracellular Distribution of PSTPIP1 |
| GO:0002221 pattern recognition receptor signaling pathway | NAS PMID:29196474 Inflammasome activation and assembly at a glance. | ACCEPT | 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. Reason: Pyrin functions as a sensor in inflammasome (PRR-type) signaling, nucleating ASC and activating caspase-1. Core process. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation |
| GO:0005874 microtubule | NAS PMID:27911804 Familial Mediterranean fever mutations lift the obligatory r... | KEEP AS NON CORE | Summary: Author-statement microtubule localization; microtubules are obligatorily required for WT pyrin inflammasome activation, and FMF mutations lift this requirement. 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. Supporting Evidence: PMID:27911804 Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:16037825 Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, v... | ACCEPT | Summary: Direct evidence that pyrin activates caspase-1 via ASC oligomerization, driving IL-1beta production. Core process. Reason: Core biological process directly demonstrated; the pyrin inflammasome positively drives IL-1beta maturation through caspase-1. Supporting Evidence: PMID:16037825 Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization |
| GO:0061702 canonical inflammasome complex | IPI PMID:16037825 Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, v... | ACCEPT | Summary: Evidence that pyrin is part of an inflammasome complex (pyrin/ASC/caspase-1). Core cellular component for the sensor. Reason: Core cellular component; pyrin is the sensor scaffold of the pyrin inflammasome, recruiting ASC and caspase-1. Supporting Evidence: PMID:16037825 Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization |
| GO:0070269 pyroptotic inflammatory response | NAS PMID:29196474 Inflammasome activation and assembly at a glance. | ACCEPT | Summary: Author-statement that pyrin participates in pyroptotic inflammatory response; consistent with pyrin inflammasome-driven caspase-1 activation and pyroptosis. Reason: Core process; the pyrin inflammasome triggers caspase-1-dependent pyroptosis. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis) |
| GO:0005515 protein binding | IPI PMID:27030597 Familial autoinflammation with neutrophilic dermatosis revea... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:27030597 Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation |
| GO:0032651 regulation of interleukin-1 beta production | IMP PMID:27030597 Familial autoinflammation with neutrophilic dermatosis revea... | ACCEPT | Summary: Mutant-phenotype evidence that pyrin activation (released from 14-3-3 inhibition) regulates IL-1beta production; PAAND/FMF mutations dysregulate this. Core process. Reason: Core biological process with IMP support; pyrin controls IL-1beta production through its inflammasome, gated by PKN/14-3-3 phosphoregulation. Supporting Evidence: PMID:27030597 a regulatory mechanism of pyrin activation |
| GO:1904270 pyroptosome complex assembly | IDA PMID:27030597 Familial autoinflammation with neutrophilic dermatosis revea... | ACCEPT | Summary: Direct evidence that activated pyrin drives assembly of the ASC pyroptosome (speck). Core process. Reason: Core biological process directly demonstrated; pyrin nucleates ASC pyroptosome/speck assembly, the central event of pyrin inflammasome activation. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an innate immune sensor that triggers PYCARD/ASC specks formation |
| GO:0005515 protein binding | IPI PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members |
| GO:0005737 cytoplasm | IDA PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | ACCEPT | Summary: Direct evidence of cytoplasmic localization of pyrin/TRIM20 in the precision-autophagy study. Core compartment. Reason: Direct experimental support for the primary cytoplasmic localization. Supporting Evidence: PMID:26347139 TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation |
| GO:0010508 positive regulation of autophagy | IDA PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | KEEP AS NON CORE | Summary: Direct evidence that pyrin/TRIM20 promotes (selective/precision) autophagy by assembling autophagy machinery and targeting inflammasome components for degradation. 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. Supporting Evidence: PMID:26347139 TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation |
| GO:0034341 response to type II interferon | IDA PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | KEEP AS NON CORE | Summary: Direct evidence linking pyrin/TRIM20 to IFN-gamma-induced (precision) autophagy; TRIM20 is among the TRIMs required for IFN-gamma-induced autophagy. Reason: Real but secondary; reflects IFN-gamma-driven autophagy context rather than pyrin's core inflammasome-sensing function. Supporting Evidence: PMID:26347139 All six TRIMs that were positive hits from the screen, TRIM1, TRIM8, TRIM20, TRIM21, TRIM22, and TRIM65 ... were required for |
| GO:1900016 negative regulation of cytokine production involved in inflammatory response | IMP PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that pyrin/TRIM20-mediated precision autophagy of inflammasome components limits inflammatory cytokine (IL-1beta/IL-18) production. Reason: Real anti-inflammatory regulatory role via autophagic degradation of inflammasome components, but secondary to pyrin's core sensor function (which is pro-inflammatory). Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt hence preventing excessive IL1B- and IL18-mediated inflammation |
| GO:1900226 negative regulation of NLRP3 inflammasome complex assembly | IMP PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that pyrin/TRIM20 negatively regulates NLRP3 inflammasome assembly by targeting NLRP3 (and NLRP1, pro-caspase-1) for autophagic degradation. Reason: Real cross-regulatory function (pyrin restrains the distinct NLRP3 inflammasome via autophagy), but secondary to pyrin's own inflammasome-sensor role. Supporting Evidence: PMID:26347139 TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro-caspase 1, for autophagic degradation |
| GO:0005515 protein binding | IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s... | KEEP AS NON CORE | 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. Reason: Records real interactions supporting pyrin's selective-autophagy receptor function, but the bare term is uninformative. Supporting Evidence: PMID:25127057 TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition |
| GO:0005829 cytosol | TAS Reactome:R-HSA-877361 | ACCEPT | Summary: Reactome curation of cytosolic localization (Pyrin binds ASC). Consistent with the core cytosolic site of inflammasome assembly. Reason: Correct cytosolic localization where pyrin nucleates the ASC inflammasome. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt an innate immune sensor that triggers PYCARD/ASC specks formation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-879221 | ACCEPT | Summary: Reactome curation of cytosolic localization (PSTPIP1 binds Pyrin). Consistent with the core cytosolic site of action. Reason: Correct cytosolic localization for pyrin-PSTPIP1 interaction in the cytosol. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization |
| GO:0032691 negative regulation of interleukin-1 beta production | IMP PMID:20041150 Missense mutations in the MEFV gene are associated with fibr... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:20041150 Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels |
| GO:0032695 negative regulation of interleukin-12 production | IMP PMID:20041150 Missense mutations in the MEFV gene are associated with fibr... | KEEP AS NON CORE | Summary: IMP from the same fibromyalgia/MEFV clinical-genetics study; negative regulation of IL-12 production. Reason: Peripheral cytokine-regulatory effect from a disease-association study; not pyrin's core function and weakly specific. Supporting Evidence: PMID:20041150 Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:16403826 Clinical and subclinical inflammation in patients with famil... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:16403826 Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations |
| GO:0071641 negative regulation of macrophage inflammatory protein 1 alpha production | IMP PMID:20041150 Missense mutations in the MEFV gene are associated with fibr... | KEEP AS NON CORE | Summary: IMP from the fibromyalgia/MEFV study; negative regulation of MIP-1alpha (CCL3) production. Reason: Highly specific peripheral cytokine-regulatory effect from a disease-association study; not a core pyrin function. Supporting Evidence: PMID:20041150 Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels |
| GO:0003779 actin binding | IDA PMID:11468188 The familial Mediterranean fever protein, pyrin, associates ... | KEEP AS NON CORE | Summary: Direct evidence that pyrin associates with actin filaments and colocalizes with polymerizing actin at ruffles/lamellipodia. Reason: Real cytoskeletal association (actin/microtubules), relevant to pyrin localization and possibly to inflammasome regulation, but not the core inflammasome-sensing molecular function. Supporting Evidence: PMID:11468188 The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments |
| GO:0005634 nucleus | IDA PMID:11115844 Alternative splicing at the MEFV locus involved in familial ... | KEEP AS NON CORE | Summary: Direct evidence that an alternatively spliced pyrin isoform (lacking exon 2) translocates to the nucleus. Reason: Nuclear localization is real but isoform-specific and not the compartment of pyrin's core cytosolic inflammasome function. Supporting Evidence: PMID:11115844 Alternative splicing at the MEFV locus ... regulates translocation of the marenostrin/pyrin protein to the nucleus |
| GO:0005875 microtubule associated complex | IDA PMID:11468188 The familial Mediterranean fever protein, pyrin, associates ... | KEEP AS NON CORE | Summary: Direct evidence that pyrin associates with microtubules. Microtubule integrity is required for WT pyrin inflammasome activation. Reason: Functionally relevant microtubule association (required for inflammasome activation in WT cells), but a supporting localization/component rather than pyrin's core inflammasome assembly. Supporting Evidence: PMID:11468188 pyrin, associates with microtubules and colocalizes with actin filaments |
| GO:0006954 inflammatory response | IDA PMID:11468188 The familial Mediterranean fever protein, pyrin, associates ... | KEEP AS NON CORE | Summary: Direct evidence implicating pyrin in the inflammatory response (colocalizes with ASC in inflammasome specks). Reason: Correct but generic parent process; the specific inflammasome/pyroptosis/IL-1beta-production annotations capture pyrin's role more precisely. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt In pre-apoptotic cells, colocalizes with PYCARD/ASC in large specks (inflammasomes) |
| GO:0008270 zinc ion binding | NAS PMID:11115844 Alternative splicing at the MEFV locus involved in familial ... | KEEP AS NON CORE | Summary: Author-statement zinc ion binding, consistent with pyrin's B-box zinc finger. 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. Supporting Evidence: file:human/MEFV/MEFV-uniprot.txt ZN_FING 370..412 |
| GO:0031267 small GTPase binding | IDA PMID:42566498 An N-terminal CDC42 T43I variant reveals the mechanism of py... | NEW | Summary: The pyrin B30.2/SPRY domain binds CDC42 directly, and this interaction controls pyrin localisation and inflammasome activation. Not present in GOA at the time of review. Reason: The canonical model has pyrin sensing RhoA only indirectly, through loss of PKN1/2-mediated phosphorylation and release of 14-3-3. Three simultaneous 2026 reports instead show a direct protein-protein interaction between the pyrin B30.2 domain and CDC42, which is a molecular function the existing annotation set does not express at all. GO has no CDC42- or Rho-specific binding term, so small GTPase binding is the most specific applicable term. Supporting Evidence: PMID:42566498 We demonstrate that the region surrounding residue T43 of CDC42 interacts with the carboxyl-terminal B30.2 domain of pyrin and regulates its localization and activation. PMID:42566498 These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42. PMID:42566500 We found that classical familial Mediterranean fever (FMF)-related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. |
| GO:0141087 positive regulation of inflammasome-mediated signaling pathway | IDA PMID:42566498 An N-terminal CDC42 T43I variant reveals the mechanism of py... | NEW | Summary: CDC42 binding to the pyrin B30.2 domain raises inflammasome output, measured as increased ASC speck formation, pyroptosis and IL-1beta/IL-18 release. Not present in GOA at the time of review. Reason: Pairs with the new GO:0031267 small GTPase binding annotation: the binding event is the molecular function, this is the process it feeds. Gain-of-function CDC42 T43I strengthens the interaction and increases activation, which is the direction-of-effect evidence the generic regulation term cannot carry. Supporting Evidence: PMID:42566498 These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42. PMID:42566500 We found that classical familial Mediterranean fever (FMF)-related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: Is direct CDC42 binding by the B30.2 domain an additional input to pyrin activation alongside the RhoA/PKN1/2/14-3-3 route, or does it supersede part of that model? And by what route do the non-FMF MEFV variants that hyperactivate pyrin CDC42-independently act?
Experiment: 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.
Experiment: 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.
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