{"gene":"MEFV","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"RhoA activates serine-threonine kinases PKN1 and PKN2, which bind and phosphorylate pyrin (MEFV protein). Phosphorylated pyrin binds 14-3-3 proteins, which block pyrin inflammasome activation. FMF-associated mutant pyrin shows substantially decreased binding to both 14-3-3 and PKN proteins, explaining constitutive IL-1β release. Defects in prenylation (as in HIDS) lead to RhoA inactivation, consequent loss of PKN1/PKN2 activity, reduced pyrin phosphorylation, and pyrin inflammasome activation.","method":"Kinase assays, Co-immunoprecipitation, phosphorylation assays, peripheral blood mononuclear cell stimulation assays, PKN1/PKN2 activation experiments in FMF and HIDS patient cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (kinase assay, Co-IP, mutant vs. wild-type comparison, patient cell functional assays) establishing a complete signaling pathway with mechanistic validation","pmids":["27270401"],"is_preprint":false},{"year":2021,"finding":"β2-microglobulin (β2MG) was identified as a novel pyrin ligand binding to the PRY/SPRY domain of pyrin/TRIM20. β2MG interaction triggers recruitment of PSTPIP1 and subsequent ASC recruitment to form the pyrin inflammasome. Caspase-1 p20 subunit (produced by activated pyrin inflammasome) also binds the PRY/SPRY domain and inhibits the pyrin-β2MG interaction as a negative feedback mechanism. The FMF-associated M694V mutation does not affect pyrin-β2MG interaction but weakens this caspase-1 p20 inhibitory feedback.","method":"Yeast two-hybrid screening, co-immunoprecipitation, co-localization imaging in HEK293 cells and monosodium urate-stimulated human neutrophils","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP and co-localization with functional inference; single lab, multiple orthogonal methods but no full reconstitution","pmids":["34880353"],"is_preprint":false},{"year":2020,"finding":"RIPK3 promotes Mefv transcriptional upregulation through negative control of the mTOR signaling pathway (independent of MAPK and NF-κB signaling and independent of pyrin dephosphorylation). Inhibition of mTOR was sufficient to upregulate Mefv expression and enhance pyrin inflammasome activation. This establishes mTOR as a negative regulator of pyrin inflammasome activation via transcriptional control of MEFV.","method":"Bone marrow-derived macrophages with RIPK3 knockout, mTOR inhibition experiments, murine peritonitis model, transcriptional assays, inflammasome activation readouts","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological intervention with defined molecular pathway placement; single lab with multiple orthogonal approaches","pmids":["32989095"],"is_preprint":false},{"year":2021,"finding":"Pathogenic MEFV variants induce caspase-1-dependent cell death (pyroptosis) accompanied by ASC speck formation and IL-1β secretion in THP-1 monocytes, confirming that disease-associated variants cause abnormal pyrin inflammasome activation. Variable degrees of spontaneous or toxin/kinase-inhibitor-induced cell death correlate with clinical phenotype severity across 32 variants.","method":"Transfection of THP-1 monocytes with 32 MEFV variants, flow cytometry-based cell death assay, ASC speck formation assay, IL-1β ELISA, caspase-1 inhibition, hierarchical cluster analysis, comparison with patient macrophage cell-based assay","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with multiple variants and caspase-1 dependence confirmed; single lab but with multiple orthogonal readouts","pmids":["33733382"],"is_preprint":false},{"year":2024,"finding":"In vitro functional analysis shows that SURF (syndrome of undifferentiated recurrent fever) patients display a distinct pyrin inflammasome activation profile from FMF: untreated SURF patients show reduced response to C. difficile toxin A (TcdA), normalized after colchicine treatment, and unlike FMF patients, SURF patients do not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. This demonstrates that pyrin dephosphorylation-dependent inflammasome activation is a specific mechanistic feature of FMF-associated pyrin mutations.","method":"Ex vivo PBMC stimulation with TcdA and UCN-01 (PKC inhibitor causing pyrin dephosphorylation), ASC speck detection by flow cytometry, IL-1β ELISA, comparison across FMF, SURF, PFAPA patient groups","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inflammasome assay across multiple patient groups with pharmacological manipulation; single study, multiple methods","pmids":["38231350"],"is_preprint":false},{"year":2000,"finding":"MEFV is expressed in a myelomonocytic-specific and proinflammatory pattern: expressed in granulocytes, eosinophils, and monocytes but not lymphocytes, and upregulated at the myelocyte stage during granulocytic differentiation. IFN-γ acts as an immediate-early inducer of MEFV expression (induction resistant to cycloheximide), and proinflammatory agents (TNF, LPS) also induce MEFV, while anti-inflammatory cytokines (IL-4, IL-10, TGF-β) inhibit expression. In granulocytes, MEFV is upregulated by IFN-γ and the combination of IFN-α and colchicine.","method":"RT-PCR, in situ hybridization, CD34 hematopoietic stem cell cultures, HL60/U937/THP-1 differentiation assays, cytokine stimulation, cycloheximide resistance test, promoter sequence analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell differentiation assays, in situ hybridization, cytokine stimulation with cycloheximide resistance), replicated across multiple cell lines and primary cells","pmids":["10807793"],"is_preprint":false},{"year":2002,"finding":"MEFV expression in peritoneal fibroblast cultures is inducible by colchicine and proinflammatory cytokines (IL-1β, TNF-α, IFN-α, IFN-γ) in parallel with induction of C5a inhibitor activity, with ~10-100-fold induction by cytokines. MEFV was also expressed in serosal tissues (peritoneal and synovial fibroblasts), not only neutrophils.","method":"RT-PCR, semi-quantitative RT-PCR, C5a-induced myeloperoxidase assay in human primary peritoneal fibroblast cultures and neutrophils with colchicine and cytokine treatments","journal":"The Israel Medical Association journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RT-PCR with functional parallel (C5a inhibitor activity), single lab, two readouts; localization to serosal fibroblasts extends known expression","pmids":["11802319"],"is_preprint":false},{"year":2002,"finding":"MEFV mRNA levels are significantly lower in FMF patients than healthy controls, with intermediate levels in healthy heterozygous carriers, demonstrating a dose-response relationship between mutation load and MEFV transcript abundance. MEFV mRNA expression inversely correlates with clinical severity score, and M694V mutation is associated with the lowest mRNA levels.","method":"Quantitative RT-PCR of MEFV transcripts in peripheral blood leukocytes from genotypically ascertained FMF patients, heterozygous carriers, and healthy controls","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — quantitative RT-PCR with genotype-stratified analysis and clinical correlation; single lab, single molecular method with multiple groups","pmids":["12384939"],"is_preprint":false},{"year":2018,"finding":"RAC1 inhibition in FMF patient PBMCs and PMNs decreases caspase-1 and IL-1β production (but not IL-6), and reduces malondialdehyde (oxidative stress marker), while catalase and glutathione activities are increased upon RAC1 inhibition. RAC1 gene expression and IL-1β levels are elevated in patients during attacks and correlate with MEFV genotype (M694V/M694V shows ~2-fold higher RAC1 expression). This places RAC1 upstream of caspase-1 activation and IL-1β production in the FMF inflammatory pathway.","method":"Real-time PCR for RAC1 expression, ex vivo PBMC/PMN cultures with RAC1 inhibitor, caspase-1 ELISA, IL-1β ELISA, oxidative stress markers (malondialdehyde, catalase, glutathione)","journal":"European cytokine network","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition with multiple downstream readouts; single lab, correlative genotype-expression data with functional inhibition assay","pmids":["30698144"],"is_preprint":false},{"year":2011,"finding":"MEFV expression depends on multiple regulatory levels including promoter variants, 3'-UTR sequences, and DNA methylation of a CpG island spanning intron 1 and exon 2. Increased methylation of exon 2 CpG island negatively correlates with MEFV expression in FMF patients. At least 15 splice variants of MEFV have been identified, some regulated by nonsense-mediated decay in cell- and transcript-specific manners. Additionally, pyrin protein is cleaved by caspase-1, with full-length pyrin less abundant than the cleaved fragment in mononuclear cells from FMF patients (opposite pattern in granulocytes).","method":"Review integrating quantitative RT-PCR studies, bisulfite sequencing for methylation analysis, splice variant identification, caspase-1 cleavage assays","journal":"Genes and immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper integrating findings from multiple studies with variable methods; individual findings lack full methodological detail in this abstract","pmids":["21776013"],"is_preprint":false},{"year":2011,"finding":"MEFV exon 2 CpG island methylation is slightly but significantly higher in FMF patients than controls, and negatively correlates with MEFV expression level in both groups (correlation stronger in FMF-only group), suggesting DNA methylation as a partial mechanism for reduced MEFV expression in FMF.","method":"Quantitative RT-PCR for MEFV expression, bisulfite sequencing for CpG methylation quantification in pediatric FMF patients and age/gender-matched healthy controls","journal":"BMC medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative methylation-expression analysis; authors note a larger dataset is needed to confirm preliminary findings","pmids":["21819621"],"is_preprint":false},{"year":2020,"finding":"Neutrophils from FMF patients with two pathogenic MEFV mutations show spontaneous ex vivo release of IL-18, S100A12, caspase-1, proteinase 3, and myeloperoxidase, as well as spontaneous CD62L (L-selectin) shedding indicating activation. This activation is independent of IL-1 signaling and NLRP3 inflammasome. A gene-dose effect is demonstrated: heterozygous carriers show intermediate levels between homozygous patients and healthy controls.","method":"Ex vivo neutrophil culture, ELISA for cytokines and granule proteins, flow cytometry for CD62L, IL-1 blockade, NLRP3 inhibition, ATP/LPS stimulation, colchicine co-culture","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts in primary patient neutrophils with pharmacological dissection; single lab with systematic genotype-stratified analysis","pmids":["32655537"],"is_preprint":false}],"current_model":"Pyrin (MEFV/TRIM20) functions as an innate immune sensor that assembles an inflammasome complex to activate caspase-1 and mature IL-1β; its activity is held in check by a RhoA→PKN1/PKN2 signaling axis that phosphorylates pyrin, enabling 14-3-3 protein binding and inflammasome suppression, while bacterial RhoA modification or loss of prenylation (as in HIDS) releases this brake—FMF-associated gain-of-function mutations in pyrin reduce PKN/14-3-3 binding, lower the threshold for inflammasome activation, and weaken negative feedback from caspase-1 p20, with mTOR signaling additionally controlling pyrin levels through transcriptional regulation of MEFV expression."},"narrative":{"mechanistic_narrative":"MEFV encodes pyrin, a myelomonocytic innate immune sensor that nucleates an inflammasome to activate caspase-1 and drive IL-1β maturation and pyroptotic cell death [PMID:27270401, PMID:33733382]. Pyrin activity is restrained by a RhoA→PKN1/PKN2 axis: active RhoA drives PKN1/PKN2 to phosphorylate pyrin, generating phospho-sites that recruit 14-3-3 proteins which block inflammasome assembly, so loss of RhoA activity (as occurs with defective prenylation in HIDS) dephosphorylates pyrin and releases the brake [PMID:27270401]. Familial Mediterranean fever (FMF)-associated gain-of-function mutations such as M694V lower the activation threshold by reducing PKN/14-3-3 binding and by weakening a caspase-1 p20 negative-feedback loop that normally competes with the β2-microglobulin ligand at the pyrin PRY/SPRY domain to limit PSTPIP1/ASC recruitment [PMID:27270401, PMID:34880353]; the dependence on pyrin dephosphorylation distinguishes FMF from related fevers [PMID:38231350]. Pyrin abundance is itself transcriptionally tuned — MEFV is induced in granulocytes, monocytes and serosal fibroblasts by IFN-γ and proinflammatory signals and repressed by anti-inflammatory cytokines [PMID:10807793, PMID:11802319] — and is held in check by mTOR signaling, with mTOR inhibition raising MEFV expression and enhancing inflammasome activation [PMID:32989095]. Pathogenic MEFV genotypes produce a gene-dose-dependent, IL-1- and NLRP3-independent neutrophil activation phenotype with spontaneous release of caspase-1, IL-18 and granule proteins [PMID:32655537].","teleology":[{"year":2000,"claim":"Established that MEFV is a regulated proinflammatory gene rather than constitutively expressed, defining its myelomonocytic expression program and cytokine responsiveness.","evidence":"RT-PCR, in situ hybridization, and cytokine stimulation across hematopoietic differentiation and cell lines","pmids":["10807793"],"confidence":"High","gaps":["Did not define the pyrin protein's molecular activity","Promoter elements mediating IFN-γ induction not mapped"]},{"year":2002,"claim":"Extended pyrin's expression and inflammatory function beyond neutrophils to serosal fibroblasts and linked it to C5a inhibitor activity.","evidence":"RT-PCR and C5a-induced myeloperoxidase assay in primary peritoneal fibroblasts and neutrophils","pmids":["11802319"],"confidence":"Medium","gaps":["Mechanistic basis of the C5a inhibitor parallel not established","Single-lab semi-quantitative readout"]},{"year":2002,"claim":"Showed that MEFV transcript abundance scales inversely with mutation load and clinical severity, framing FMF partly as a dosage/expression phenomenon.","evidence":"Quantitative RT-PCR in genotype-stratified FMF patients, carriers, and controls","pmids":["12384939"],"confidence":"Medium","gaps":["Correlative; does not establish causal direction between low mRNA and disease","Mechanism of reduced transcript not identified here"]},{"year":2011,"claim":"Proposed multilayered MEFV regulation (promoter variants, splice variants/NMD, CpG methylation, caspase-1 cleavage of pyrin) integrating prior data.","evidence":"Review integrating RT-PCR, bisulfite sequencing, splice variant, and cleavage studies","pmids":["21776013"],"confidence":"Low","gaps":["Review-level synthesis without primary methodological detail","Functional consequence of pyrin cleavage products unresolved"]},{"year":2011,"claim":"Provided direct correlative evidence that exon 2 CpG island methylation partially explains reduced MEFV expression in FMF.","evidence":"Quantitative RT-PCR and bisulfite sequencing in pediatric FMF patients and matched controls","pmids":["21819621"],"confidence":"Low","gaps":["Authors note a larger dataset needed to confirm","Effect size small; causal contribution to disease unclear"]},{"year":2016,"claim":"Resolved how pyrin activity is normally restrained, defining the RhoA→PKN1/PKN2→phospho-pyrin→14-3-3 brake and explaining both FMF (reduced PKN/14-3-3 binding) and HIDS (loss of prenylation/RhoA) mechanistically.","evidence":"Kinase and phosphorylation assays, Co-IP, mutant vs wild-type comparison, and FMF/HIDS patient cell functional assays","pmids":["27270401"],"confidence":"High","gaps":["Does not define the activating ligand or assembly trigger of the inflammasome","Structural basis of 14-3-3 vs PKN engagement not resolved"]},{"year":2018,"claim":"Placed RAC1 upstream of caspase-1/IL-1β output and linked it to oxidative stress, expanding the Rho-family GTPase context of pyrin regulation.","evidence":"RAC1 inhibition in patient PBMCs/PMNs with caspase-1, IL-1β, and oxidative stress readouts","pmids":["30698144"],"confidence":"Medium","gaps":["Direct molecular link between RAC1 and pyrin not demonstrated","Correlative genotype-expression data only"]},{"year":2020,"claim":"Identified mTOR as a transcriptional negative regulator of MEFV (downstream of RIPK3), connecting metabolic signaling to inflammasome priming.","evidence":"RIPK3 knockout BMDMs, mTOR inhibition, and murine peritonitis with transcriptional and inflammasome readouts","pmids":["32989095"],"confidence":"Medium","gaps":["Transcription factors linking mTOR to MEFV not identified","Demonstrated in mouse; human relevance not confirmed here"]},{"year":2020,"claim":"Showed pathogenic MEFV drives spontaneous neutrophil activation independent of IL-1 and NLRP3 with a clear gene-dose effect, broadening the disease effector beyond IL-1β.","evidence":"Ex vivo patient neutrophil assays with ELISA, flow cytometry, and pharmacological dissection","pmids":["32655537"],"confidence":"Medium","gaps":["Mechanism of IL-1-independent granule release unresolved","Whether this reflects pyrin inflammasome or a parallel pathway unclear"]},{"year":2021,"claim":"Identified β2-microglobulin as a PRY/SPRY-domain ligand triggering PSTPIP1/ASC recruitment, and defined caspase-1 p20 as a competing negative-feedback ligand weakened by M694V.","evidence":"Yeast two-hybrid, Co-IP, and co-localization in HEK293 cells and urate-stimulated neutrophils","pmids":["34880353"],"confidence":"Medium","gaps":["No full reconstitution of the assembly step","Physiological relevance of β2MG as the activating signal in vivo not established"]},{"year":2021,"claim":"Demonstrated across 32 variants that pathogenic MEFV causes caspase-1-dependent pyroptosis and ASC speck formation, linking variant biochemistry to clinical severity.","evidence":"THP-1 transfection with cell death, ASC speck, IL-1β, and caspase-1 inhibition assays plus clustering","pmids":["33733382"],"confidence":"Medium","gaps":["Overexpression system may not reflect endogenous thresholds","Mechanism distinguishing variant severity not molecularly resolved"]},{"year":2024,"claim":"Established that pyrin-dephosphorylation-dependent inflammasome activation is a feature specific to FMF mutations, distinguishing FMF from SURF and other fevers.","evidence":"Ex vivo PBMC stimulation with TcdA and UCN-01 across FMF, SURF, and PFAPA patient groups","pmids":["38231350"],"confidence":"Medium","gaps":["Molecular basis of the SURF activation profile unknown","Causative gene(s) in SURF not addressed"]},{"year":null,"claim":"How the physiological activating ligand, the RhoA/PKN brake, and the β2MG/caspase-1 p20 PRY-SPRY interactions are integrated into a single regulated assembly mechanism in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted structural model of pyrin inflammasome assembly","Relationship between transcriptional (mTOR/methylation) and post-translational (phospho/14-3-3) control not unified","IL-1-independent neutrophil effector mechanism uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5,7]}],"complexes":["pyrin inflammasome"],"partners":["PKN1","PKN2","YWHA (14-3-3)","B2M","PSTPIP1","PYCARD (ASC)","CASP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15553","full_name":"Pyrin","aliases":["Marenostrin"],"length_aa":781,"mass_kda":86.4,"function":"Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma (PubMed:10807793, PubMed:11468188, PubMed:16037825, PubMed:16785446, PubMed:17431422, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923, PubMed:26347139, PubMed:27030597, PubMed:28835462). Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy (PubMed:16785446, PubMed:17431422, PubMed:26347139). Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:16785446, PubMed:17431422, PubMed:26347139). However, it can also have a positive effect in the inflammatory pathway, acting as an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production (PubMed:16037825, PubMed:27030597, PubMed:28835462). Together with AIM2, also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). It is required for PSTPIP1-induced PYCARD/ASC oligomerization and inflammasome formation (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923). Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15553/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEFV","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEFV","total_profiled":1310},"omim":[{"mim_id":"617321","title":"YAO SYNDROME; YAOS","url":"https://www.omim.org/entry/617321"},{"mim_id":"614684","title":"HYPERTELORISM AND OTHER FACIAL DYSMORPHISM, BRACHYDACTYLY, GENITAL ABNORMALITIES, IMPAIRED INTELLECTUAL DEVELOPMENT, AND RECURRENT INFLAMMATORY EPISODES","url":"https://www.omim.org/entry/614684"},{"mim_id":"612677","title":"PYRIN AND HIN DOMAIN FAMILY, MEMBER 1; PYHIN1","url":"https://www.omim.org/entry/612677"},{"mim_id":"609665","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 14; NLRP14","url":"https://www.omim.org/entry/609665"},{"mim_id":"609664","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 11; NLRP11","url":"https://www.omim.org/entry/609664"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":5.1},{"tissue":"lung","ntpm":3.9},{"tissue":"lymphoid tissue","ntpm":8.5}],"url":"https://www.proteinatlas.org/search/MEFV"},"hgnc":{"alias_symbol":["FMF","TRIM20"],"prev_symbol":["MEF"]},"alphafold":{"accession":"O15553","domains":[{"cath_id":"1.10.533.10","chopping":"6-94","consensus_level":"high","plddt":87.457,"start":6,"end":94},{"cath_id":"2.60.120.920","chopping":"588-774","consensus_level":"high","plddt":94.6668,"start":588,"end":774},{"cath_id":"1.20.5","chopping":"414-541","consensus_level":"medium","plddt":94.8016,"start":414,"end":541}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15553","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15553-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15553-F1-predicted_aligned_error_v6.png","plddt_mean":72.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEFV","jax_strain_url":"https://www.jax.org/strain/search?query=MEFV"},"sequence":{"accession":"O15553","fasta_url":"https://rest.uniprot.org/uniprotkb/O15553.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15553/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15553"}},"corpus_meta":[{"pmid":"27270401","id":"PMC_27270401","title":"Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27270401","citation_count":449,"is_preprint":false},{"pmid":"11464238","id":"PMC_11464238","title":"The spectrum of Familial Mediterranean Fever (FMF) mutations.","date":"2001","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/11464238","citation_count":407,"is_preprint":false},{"pmid":"10807793","id":"PMC_10807793","title":"The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10807793","citation_count":328,"is_preprint":false},{"pmid":"9668175","id":"PMC_9668175","title":"Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9668175","citation_count":215,"is_preprint":false},{"pmid":"10737995","id":"PMC_10737995","title":"The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?","date":"2000","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/10737995","citation_count":137,"is_preprint":false},{"pmid":"10980540","id":"PMC_10980540","title":"MEFV mutations in Behçet's disease.","date":"2000","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/10980540","citation_count":123,"is_preprint":false},{"pmid":"15720245","id":"PMC_15720245","title":"Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update.","date":"2005","source":"Current drug targets. 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bind and phosphorylate pyrin (MEFV protein). Phosphorylated pyrin binds 14-3-3 proteins, which block pyrin inflammasome activation. FMF-associated mutant pyrin shows substantially decreased binding to both 14-3-3 and PKN proteins, explaining constitutive IL-1β release. Defects in prenylation (as in HIDS) lead to RhoA inactivation, consequent loss of PKN1/PKN2 activity, reduced pyrin phosphorylation, and pyrin inflammasome activation.\",\n      \"method\": \"Kinase assays, Co-immunoprecipitation, phosphorylation assays, peripheral blood mononuclear cell stimulation assays, PKN1/PKN2 activation experiments in FMF and HIDS patient cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (kinase assay, Co-IP, mutant vs. wild-type comparison, patient cell functional assays) establishing a complete signaling pathway with mechanistic validation\",\n      \"pmids\": [\"27270401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"β2-microglobulin (β2MG) was identified as a novel pyrin ligand binding to the PRY/SPRY domain of pyrin/TRIM20. β2MG interaction triggers recruitment of PSTPIP1 and subsequent ASC recruitment to form the pyrin inflammasome. Caspase-1 p20 subunit (produced by activated pyrin inflammasome) also binds the PRY/SPRY domain and inhibits the pyrin-β2MG interaction as a negative feedback mechanism. The FMF-associated M694V mutation does not affect pyrin-β2MG interaction but weakens this caspase-1 p20 inhibitory feedback.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, co-localization imaging in HEK293 cells and monosodium urate-stimulated human neutrophils\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus Co-IP and co-localization with functional inference; single lab, multiple orthogonal methods but no full reconstitution\",\n      \"pmids\": [\"34880353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RIPK3 promotes Mefv transcriptional upregulation through negative control of the mTOR signaling pathway (independent of MAPK and NF-κB signaling and independent of pyrin dephosphorylation). Inhibition of mTOR was sufficient to upregulate Mefv expression and enhance pyrin inflammasome activation. This establishes mTOR as a negative regulator of pyrin inflammasome activation via transcriptional control of MEFV.\",\n      \"method\": \"Bone marrow-derived macrophages with RIPK3 knockout, mTOR inhibition experiments, murine peritonitis model, transcriptional assays, inflammasome activation readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological intervention with defined molecular pathway placement; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"32989095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic MEFV variants induce caspase-1-dependent cell death (pyroptosis) accompanied by ASC speck formation and IL-1β secretion in THP-1 monocytes, confirming that disease-associated variants cause abnormal pyrin inflammasome activation. Variable degrees of spontaneous or toxin/kinase-inhibitor-induced cell death correlate with clinical phenotype severity across 32 variants.\",\n      \"method\": \"Transfection of THP-1 monocytes with 32 MEFV variants, flow cytometry-based cell death assay, ASC speck formation assay, IL-1β ELISA, caspase-1 inhibition, hierarchical cluster analysis, comparison with patient macrophage cell-based assay\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with multiple variants and caspase-1 dependence confirmed; single lab but with multiple orthogonal readouts\",\n      \"pmids\": [\"33733382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In vitro functional analysis shows that SURF (syndrome of undifferentiated recurrent fever) patients display a distinct pyrin inflammasome activation profile from FMF: untreated SURF patients show reduced response to C. difficile toxin A (TcdA), normalized after colchicine treatment, and unlike FMF patients, SURF patients do not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. This demonstrates that pyrin dephosphorylation-dependent inflammasome activation is a specific mechanistic feature of FMF-associated pyrin mutations.\",\n      \"method\": \"Ex vivo PBMC stimulation with TcdA and UCN-01 (PKC inhibitor causing pyrin dephosphorylation), ASC speck detection by flow cytometry, IL-1β ELISA, comparison across FMF, SURF, PFAPA patient groups\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inflammasome assay across multiple patient groups with pharmacological manipulation; single study, multiple methods\",\n      \"pmids\": [\"38231350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MEFV is expressed in a myelomonocytic-specific and proinflammatory pattern: expressed in granulocytes, eosinophils, and monocytes but not lymphocytes, and upregulated at the myelocyte stage during granulocytic differentiation. IFN-γ acts as an immediate-early inducer of MEFV expression (induction resistant to cycloheximide), and proinflammatory agents (TNF, LPS) also induce MEFV, while anti-inflammatory cytokines (IL-4, IL-10, TGF-β) inhibit expression. In granulocytes, MEFV is upregulated by IFN-γ and the combination of IFN-α and colchicine.\",\n      \"method\": \"RT-PCR, in situ hybridization, CD34 hematopoietic stem cell cultures, HL60/U937/THP-1 differentiation assays, cytokine stimulation, cycloheximide resistance test, promoter sequence analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell differentiation assays, in situ hybridization, cytokine stimulation with cycloheximide resistance), replicated across multiple cell lines and primary cells\",\n      \"pmids\": [\"10807793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MEFV expression in peritoneal fibroblast cultures is inducible by colchicine and proinflammatory cytokines (IL-1β, TNF-α, IFN-α, IFN-γ) in parallel with induction of C5a inhibitor activity, with ~10-100-fold induction by cytokines. MEFV was also expressed in serosal tissues (peritoneal and synovial fibroblasts), not only neutrophils.\",\n      \"method\": \"RT-PCR, semi-quantitative RT-PCR, C5a-induced myeloperoxidase assay in human primary peritoneal fibroblast cultures and neutrophils with colchicine and cytokine treatments\",\n      \"journal\": \"The Israel Medical Association journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RT-PCR with functional parallel (C5a inhibitor activity), single lab, two readouts; localization to serosal fibroblasts extends known expression\",\n      \"pmids\": [\"11802319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MEFV mRNA levels are significantly lower in FMF patients than healthy controls, with intermediate levels in healthy heterozygous carriers, demonstrating a dose-response relationship between mutation load and MEFV transcript abundance. MEFV mRNA expression inversely correlates with clinical severity score, and M694V mutation is associated with the lowest mRNA levels.\",\n      \"method\": \"Quantitative RT-PCR of MEFV transcripts in peripheral blood leukocytes from genotypically ascertained FMF patients, heterozygous carriers, and healthy controls\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — quantitative RT-PCR with genotype-stratified analysis and clinical correlation; single lab, single molecular method with multiple groups\",\n      \"pmids\": [\"12384939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAC1 inhibition in FMF patient PBMCs and PMNs decreases caspase-1 and IL-1β production (but not IL-6), and reduces malondialdehyde (oxidative stress marker), while catalase and glutathione activities are increased upon RAC1 inhibition. RAC1 gene expression and IL-1β levels are elevated in patients during attacks and correlate with MEFV genotype (M694V/M694V shows ~2-fold higher RAC1 expression). This places RAC1 upstream of caspase-1 activation and IL-1β production in the FMF inflammatory pathway.\",\n      \"method\": \"Real-time PCR for RAC1 expression, ex vivo PBMC/PMN cultures with RAC1 inhibitor, caspase-1 ELISA, IL-1β ELISA, oxidative stress markers (malondialdehyde, catalase, glutathione)\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition with multiple downstream readouts; single lab, correlative genotype-expression data with functional inhibition assay\",\n      \"pmids\": [\"30698144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MEFV expression depends on multiple regulatory levels including promoter variants, 3'-UTR sequences, and DNA methylation of a CpG island spanning intron 1 and exon 2. Increased methylation of exon 2 CpG island negatively correlates with MEFV expression in FMF patients. At least 15 splice variants of MEFV have been identified, some regulated by nonsense-mediated decay in cell- and transcript-specific manners. Additionally, pyrin protein is cleaved by caspase-1, with full-length pyrin less abundant than the cleaved fragment in mononuclear cells from FMF patients (opposite pattern in granulocytes).\",\n      \"method\": \"Review integrating quantitative RT-PCR studies, bisulfite sequencing for methylation analysis, splice variant identification, caspase-1 cleavage assays\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper integrating findings from multiple studies with variable methods; individual findings lack full methodological detail in this abstract\",\n      \"pmids\": [\"21776013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MEFV exon 2 CpG island methylation is slightly but significantly higher in FMF patients than controls, and negatively correlates with MEFV expression level in both groups (correlation stronger in FMF-only group), suggesting DNA methylation as a partial mechanism for reduced MEFV expression in FMF.\",\n      \"method\": \"Quantitative RT-PCR for MEFV expression, bisulfite sequencing for CpG methylation quantification in pediatric FMF patients and age/gender-matched healthy controls\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative methylation-expression analysis; authors note a larger dataset is needed to confirm preliminary findings\",\n      \"pmids\": [\"21819621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neutrophils from FMF patients with two pathogenic MEFV mutations show spontaneous ex vivo release of IL-18, S100A12, caspase-1, proteinase 3, and myeloperoxidase, as well as spontaneous CD62L (L-selectin) shedding indicating activation. This activation is independent of IL-1 signaling and NLRP3 inflammasome. A gene-dose effect is demonstrated: heterozygous carriers show intermediate levels between homozygous patients and healthy controls.\",\n      \"method\": \"Ex vivo neutrophil culture, ELISA for cytokines and granule proteins, flow cytometry for CD62L, IL-1 blockade, NLRP3 inhibition, ATP/LPS stimulation, colchicine co-culture\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts in primary patient neutrophils with pharmacological dissection; single lab with systematic genotype-stratified analysis\",\n      \"pmids\": [\"32655537\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Pyrin (MEFV/TRIM20) functions as an innate immune sensor that assembles an inflammasome complex to activate caspase-1 and mature IL-1β; its activity is held in check by a RhoA→PKN1/PKN2 signaling axis that phosphorylates pyrin, enabling 14-3-3 protein binding and inflammasome suppression, while bacterial RhoA modification or loss of prenylation (as in HIDS) releases this brake—FMF-associated gain-of-function mutations in pyrin reduce PKN/14-3-3 binding, lower the threshold for inflammasome activation, and weaken negative feedback from caspase-1 p20, with mTOR signaling additionally controlling pyrin levels through transcriptional regulation of MEFV expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEFV encodes pyrin, a myelomonocytic innate immune sensor that nucleates an inflammasome to activate caspase-1 and drive IL-1β maturation and pyroptotic cell death [#0, #3]. Pyrin activity is restrained by a RhoA→PKN1/PKN2 axis: active RhoA drives PKN1/PKN2 to phosphorylate pyrin, generating phospho-sites that recruit 14-3-3 proteins which block inflammasome assembly, so loss of RhoA activity (as occurs with defective prenylation in HIDS) dephosphorylates pyrin and releases the brake [#0]. Familial Mediterranean fever (FMF)-associated gain-of-function mutations such as M694V lower the activation threshold by reducing PKN/14-3-3 binding and by weakening a caspase-1 p20 negative-feedback loop that normally competes with the β2-microglobulin ligand at the pyrin PRY/SPRY domain to limit PSTPIP1/ASC recruitment [#0, #1]; the dependence on pyrin dephosphorylation distinguishes FMF from related fevers [#4]. Pyrin abundance is itself transcriptionally tuned — MEFV is induced in granulocytes, monocytes and serosal fibroblasts by IFN-γ and proinflammatory signals and repressed by anti-inflammatory cytokines [#5, #6] — and is held in check by mTOR signaling, with mTOR inhibition raising MEFV expression and enhancing inflammasome activation [#2]. Pathogenic MEFV genotypes produce a gene-dose-dependent, IL-1- and NLRP3-independent neutrophil activation phenotype with spontaneous release of caspase-1, IL-18 and granule proteins [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that MEFV is a regulated proinflammatory gene rather than constitutively expressed, defining its myelomonocytic expression program and cytokine responsiveness.\",\n      \"evidence\": \"RT-PCR, in situ hybridization, and cytokine stimulation across hematopoietic differentiation and cell lines\",\n      \"pmids\": [\"10807793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the pyrin protein's molecular activity\", \"Promoter elements mediating IFN-γ induction not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended pyrin's expression and inflammatory function beyond neutrophils to serosal fibroblasts and linked it to C5a inhibitor activity.\",\n      \"evidence\": \"RT-PCR and C5a-induced myeloperoxidase assay in primary peritoneal fibroblasts and neutrophils\",\n      \"pmids\": [\"11802319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of the C5a inhibitor parallel not established\", \"Single-lab semi-quantitative readout\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that MEFV transcript abundance scales inversely with mutation load and clinical severity, framing FMF partly as a dosage/expression phenomenon.\",\n      \"evidence\": \"Quantitative RT-PCR in genotype-stratified FMF patients, carriers, and controls\",\n      \"pmids\": [\"12384939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative; does not establish causal direction between low mRNA and disease\", \"Mechanism of reduced transcript not identified here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Proposed multilayered MEFV regulation (promoter variants, splice variants/NMD, CpG methylation, caspase-1 cleavage of pyrin) integrating prior data.\",\n      \"evidence\": \"Review integrating RT-PCR, bisulfite sequencing, splice variant, and cleavage studies\",\n      \"pmids\": [\"21776013\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review-level synthesis without primary methodological detail\", \"Functional consequence of pyrin cleavage products unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided direct correlative evidence that exon 2 CpG island methylation partially explains reduced MEFV expression in FMF.\",\n      \"evidence\": \"Quantitative RT-PCR and bisulfite sequencing in pediatric FMF patients and matched controls\",\n      \"pmids\": [\"21819621\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Authors note a larger dataset needed to confirm\", \"Effect size small; causal contribution to disease unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how pyrin activity is normally restrained, defining the RhoA→PKN1/PKN2→phospho-pyrin→14-3-3 brake and explaining both FMF (reduced PKN/14-3-3 binding) and HIDS (loss of prenylation/RhoA) mechanistically.\",\n      \"evidence\": \"Kinase and phosphorylation assays, Co-IP, mutant vs wild-type comparison, and FMF/HIDS patient cell functional assays\",\n      \"pmids\": [\"27270401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the activating ligand or assembly trigger of the inflammasome\", \"Structural basis of 14-3-3 vs PKN engagement not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed RAC1 upstream of caspase-1/IL-1β output and linked it to oxidative stress, expanding the Rho-family GTPase context of pyrin regulation.\",\n      \"evidence\": \"RAC1 inhibition in patient PBMCs/PMNs with caspase-1, IL-1β, and oxidative stress readouts\",\n      \"pmids\": [\"30698144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between RAC1 and pyrin not demonstrated\", \"Correlative genotype-expression data only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified mTOR as a transcriptional negative regulator of MEFV (downstream of RIPK3), connecting metabolic signaling to inflammasome priming.\",\n      \"evidence\": \"RIPK3 knockout BMDMs, mTOR inhibition, and murine peritonitis with transcriptional and inflammasome readouts\",\n      \"pmids\": [\"32989095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors linking mTOR to MEFV not identified\", \"Demonstrated in mouse; human relevance not confirmed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed pathogenic MEFV drives spontaneous neutrophil activation independent of IL-1 and NLRP3 with a clear gene-dose effect, broadening the disease effector beyond IL-1β.\",\n      \"evidence\": \"Ex vivo patient neutrophil assays with ELISA, flow cytometry, and pharmacological dissection\",\n      \"pmids\": [\"32655537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IL-1-independent granule release unresolved\", \"Whether this reflects pyrin inflammasome or a parallel pathway unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified β2-microglobulin as a PRY/SPRY-domain ligand triggering PSTPIP1/ASC recruitment, and defined caspase-1 p20 as a competing negative-feedback ligand weakened by M694V.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and co-localization in HEK293 cells and urate-stimulated neutrophils\",\n      \"pmids\": [\"34880353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full reconstitution of the assembly step\", \"Physiological relevance of β2MG as the activating signal in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated across 32 variants that pathogenic MEFV causes caspase-1-dependent pyroptosis and ASC speck formation, linking variant biochemistry to clinical severity.\",\n      \"evidence\": \"THP-1 transfection with cell death, ASC speck, IL-1β, and caspase-1 inhibition assays plus clustering\",\n      \"pmids\": [\"33733382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not reflect endogenous thresholds\", \"Mechanism distinguishing variant severity not molecularly resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that pyrin-dephosphorylation-dependent inflammasome activation is a feature specific to FMF mutations, distinguishing FMF from SURF and other fevers.\",\n      \"evidence\": \"Ex vivo PBMC stimulation with TcdA and UCN-01 across FMF, SURF, and PFAPA patient groups\",\n      \"pmids\": [\"38231350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the SURF activation profile unknown\", \"Causative gene(s) in SURF not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the physiological activating ligand, the RhoA/PKN brake, and the β2MG/caspase-1 p20 PRY-SPRY interactions are integrated into a single regulated assembly mechanism in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted structural model of pyrin inflammasome assembly\", \"Relationship between transcriptional (mTOR/methylation) and post-translational (phospho/14-3-3) control not unified\", \"IL-1-independent neutrophil effector mechanism uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5, 7]}\n    ],\n    \"complexes\": [\"pyrin inflammasome\"],\n    \"partners\": [\"PKN1\", \"PKN2\", \"YWHA (14-3-3)\", \"B2M\", \"PSTPIP1\", \"PYCARD (ASC)\", \"CASP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}