{"gene":"PFN1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2021,"finding":"ALS-linked PFN1 variants G118V and M114T show differential binding to select formin proteins compared to wild-type PFN1, and both variants augment formin-mediated actin assembly relative to WT PFN1. Molecular dynamics simulations revealed mutation-induced changes in internal dynamic couplings within an alpha helix of PFN1 that directly contacts both actin and polyproline. In contrast, C71G is more severely destabilized, resulting in reduced protein expression and loss-of-function in actin assembly.","method":"Unbiased proteomics (differential interactome), in vitro actin assembly assays, molecular dynamics simulations, cell-based expression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (proteomics, in vitro reconstitution, MD simulations, cell-based assays) in a single rigorous study","pmids":["34074767"],"is_preprint":false},{"year":2016,"finding":"Transgenic mice expressing ALS-associated mutant PFN1 (C71G), but not wild-type PFN1, develop progressive motor neuron loss, muscle weakness, and paralysis. Mutant PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM1 levels in motor neurons. Acceleration of motor neuron degeneration precedes accumulation of mutant PFN1 aggregates, indicating aggregation is not the trigger of disease onset.","method":"Transgenic mouse model (gain-of-function), histopathology, immunostaining, behavioral testing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-controlled transgenic mouse model with multiple phenotypic readouts, replicated across multiple lines","pmids":["27681617"],"is_preprint":false},{"year":2019,"finding":"PFN1 interaction with VASP is promoted by cell-substrate adhesion and requires downregulation of PKA activity. PKA-mediated phosphorylation of PFN1 at Ser137 negatively regulates the PFN1-VASP interaction and contributes to anti-migratory effects of cAMP/PKA agonists.","method":"Mutagenesis in overexpression and knockdown-rescue settings, co-immunoprecipitation, cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with knockdown-rescue and functional cell migration assays, multiple orthogonal methods in one study","pmids":["30814249"],"is_preprint":false},{"year":2024,"finding":"ALS-linked mutant PFN1 (G118V, M114T, C71G) expressed in iPSC-derived microglia causes lipid dysmetabolism, autophagy dysregulation, and deficient phagocytosis. Mutant PFN1 exhibits enhanced binding affinity for PI3P (a signaling molecule in autophagic/endocytic processing). Rapamycin rescued phagocytic dysfunction, implicating a gain-of-toxic function in autophagic and endo-lysosomal pathways.","method":"iPSC-derived microglia (iMGs), phagocytosis assays, PI3P binding assays, rapamycin rescue experiments, lipidomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — human iPSC-derived cell model with multiple orthogonal functional assays and pharmacological rescue in a peer-reviewed study","pmids":["38509062"],"is_preprint":false},{"year":2022,"finding":"The lncRNA UCA1 physically binds USP14 (a deubiquitinating enzyme) and functions as a scaffold to recruit USP14 to PFN1, inhibiting ubiquitination-dependent degradation of PFN1 and prolonging its half-life, thereby activating the RhoA/ROCK pathway and inducing ROS production in endothelial cells.","method":"Coculture system, exosome extraction, co-immunoprecipitation, ubiquitination assays, ROS measurement","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mechanistic Co-IP and ubiquitination assays in a single lab, multiple methods but not independently replicated","pmids":["36160709"],"is_preprint":false},{"year":2021,"finding":"SH3BGRL promotes degradation of PFN1 by accelerating translation of the E3 ubiquitin ligase STUB1 (via interaction with ribosomal proteins) and/or enhancing the interaction of PFN1 with STUB1, leading to proteasomal degradation of PFN1. Loss of PFN1 activates AKT, NF-kB, and WNT signaling pathways, while forced PFN1 expression neutralizes SH3BGRL-induced metastasis with PTEN upregulation and PI3K-AKT inactivation.","method":"Co-immunoprecipitation, protein degradation assays, ribosome interaction studies, in vitro and in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple mechanistic assays (Co-IP, translation assays, rescue experiments, in vivo) in single lab","pmids":["34331014"],"is_preprint":false},{"year":2022,"finding":"PFN1 mutation M114T destabilizes the protein and deregulates the RAB9-mediated alternative autophagy pathway involved in clearance of damaged mitochondria. Motor neurons expressing M114T mutant PFN1 show mitochondrial abnormalities in vivo.","method":"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy pathway marker analysis, mitochondrial morphology assessment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells plus in vivo model, multiple readouts but single lab","pmids":["35628504"],"is_preprint":false},{"year":2017,"finding":"In a Drosophila model, expression of wild-type human PFN1 in motor neurons increases ghost boutons, active zone density, F-actin content, and filopodia formation at larval NMJs. ALS-causative PFN1 mutants display less pronounced NMJ phenotypes, suggesting partial loss of function in promoting NMJ remodeling and actin polymerization.","method":"Drosophila transgenic model, NMJ morphology analysis, locomotion and lifespan assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila model with quantitative morphological and functional readouts, single lab","pmids":["28379367"],"is_preprint":false},{"year":2020,"finding":"A frameshift mutation (D107Rfs*3) in PFN1 causing truncation of the C-terminal portion of the protein leads to a loss of function of profilin 1 activity. In vitro osteoclastogenesis from mutation carriers showed higher numbers of osteoclasts with PDB-like features, and PFN1 silencing in murine bone marrow-derived monocytes recapitulated the phenotype, suggesting enhanced osteoclast motility and actin ring formation.","method":"Whole exome sequencing, in vitro osteoclastogenesis from PBMCs, PFN1 silencing in murine bone marrow-derived monocytes","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — patient-derived functional assays plus murine knockdown model, single lab, two orthogonal approaches","pmids":["32392277"],"is_preprint":false},{"year":2022,"finding":"PFN1 inhibits myogenic differentiation of bovine skeletal muscle satellite cells via binding to Cdc42 (identified by co-immunoprecipitation and mass spectrometry). PFN1 activates Cdc42, which increases phosphorylation of PAK, which in turn activates JNK phosphorylation, and both PAK and JNK are inhibitors of myogenic differentiation.","method":"Immunoprecipitation combined with mass spectrometry, kinase phosphorylation assays, overexpression/knockdown experiments","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP/MS to identify binding partner plus signaling cascade verification, single lab","pmids":["36291059"],"is_preprint":false},{"year":2020,"finding":"Detergent-insoluble PFN1 inclusions are the first detected pathology in otherwise asymptomatic transgenic rats expressing mutant human PFN1 (C71G), preceding motor neuron loss and muscle atrophy, suggesting protein aggregation is involved in the neurodegeneration.","method":"Human genomic DNA transgenic rats, detergent fractionation, histopathology, behavioral testing","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genomic transgenic rat model with careful temporal analysis, single lab","pmids":["32754913"],"is_preprint":false},{"year":2023,"finding":"Intramuscular administration of detergent-insoluble materials from paralyzed mutant PFN1 transgenic rats accelerated development of PFN1 inclusions and ALS-like phenotypes in asymptomatic recipient mutant PFN1 rats (seeding effect). Pathogenic PFN1 exhibited enhanced affinity for molecular chaperone DNAJB6, leading to sequestration of DNAJB6 within protein inclusions.","method":"Intrinsic seeding experiment in transgenic rats, detergent fractionation, co-immunoprecipitation for DNAJB6 interaction","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo seeding experiment with appropriate controls plus binding assay, single lab","pmids":["37817804"],"is_preprint":false},{"year":2026,"finding":"FBXL4 (an F-box protein) interacts with PFN1 and promotes K48-linked ubiquitination of PFN1 at lysine 70, leading to its proteasomal degradation and preservation of sarcomeric integrity in cardiomyocytes. Loss of FBXL4 leads to PFN1 accumulation and cardiac dysfunction.","method":"Co-immunoprecipitation, ubiquitination site mapping (K70), AAV-mediated knockdown/overexpression in mouse hearts, hiPSC-derived cardiomyocytes","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific ubiquitination mapping at K70, multiple in vivo and in vitro models, AAV rescue experiments, hiPSC validation","pmids":["41589689"],"is_preprint":false},{"year":2026,"finding":"PFN1 interacts with KSHV helicase ORF44, and the E3 ubiquitin ligase TRIM37 facilitates polyubiquitination of PFN1 at lysine 116. This ubiquitinated PFN1 serves as a recognition motif for the cargo receptor SQSTM1/p62, leading to autophagic degradation of ORF44 and inhibition of KSHV lytic replication.","method":"Co-immunoprecipitation, ubiquitination site mapping (K116), autophagy-lysosomal degradation assays, KSHV replication assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic Co-IP, site-specific ubiquitination mapping, functional viral replication assays, single lab","pmids":["42260986"],"is_preprint":false},{"year":2025,"finding":"A PFN1 L112P mutation in osteoclasts leads to enhanced actin ring-like structures at bone surfaces without affecting NF-κB activation, suggesting a specific role of PFN1 in actin ring formation during osteoclast function independent of NF-κB signaling.","method":"Heterozygous knock-in mouse model (Pfn1 L112P), osteoclast culture, immunofluorescence for actin rings, NF-κB activation assays","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with specific cellular readouts, single lab","pmids":["40458045"],"is_preprint":false},{"year":2024,"finding":"Oleic acid increases acetylation of PFN1 and promotes prostate cancer cell migration/invasion with enhanced PFN1 and FLNA localization to the leading edge. EPA decreases PFN1 acetylation and impedes lamellipodia/filopodia formation by reducing PFN1 localization to the leading edge.","method":"Global acetylome profiling, immunofluorescence, cell migration/invasion assays","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — acetylome profiling with single immunofluorescence readout, no direct mutagenesis of acetylation sites, single lab","pmids":["38430206"],"is_preprint":false},{"year":2019,"finding":"Computational and simulation analysis of the PFN1–polyproline-10 binding interface confirmed that residues W3, H133, and S137 of PFN1 form favorable hydrogen bonds with polyproline-10, consistent with crystallographic binding structures and suggesting a zipping process during binding.","method":"Umbrella sampling (PMF), molecular dynamics simulations, steered molecular dynamics","journal":"The Journal of chemical physics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational only, no experimental validation of specific residue mutations in this paper","pmids":["30621420"],"is_preprint":false},{"year":2015,"finding":"Nicotine induces PFN1 overexpression in mouse elongated spermatids via hypomethylation of the Pfn1 promoter, leading to increased actin polymerization and elevated sperm motility.","method":"2D gel electrophoresis, mass spectrometry, bisulfite sequencing (promoter methylation), sperm motility analysis","journal":"Andrology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative promoter methylation analysis without direct functional rescue experiments linking Pfn1 overexpression to motility","pmids":["26311342"],"is_preprint":false}],"current_model":"PFN1 (profilin-1) is a small actin-binding protein that promotes formin-mediated actin polymerization and regulates cytoskeletal dynamics by binding monomeric actin and polyproline-motif-containing proteins (such as VASP and formins); its activity is post-translationally regulated by PKA-mediated phosphorylation at Ser137 (inhibiting VASP interaction), K48-linked ubiquitination at K70 by FBXL4 (promoting proteasomal degradation), and K116 ubiquitination by TRIM37 (enabling SQSTM1/p62-mediated selective autophagy); ALS-linked mutations (C71G, M114T, G118V) destabilize the protein or alter its binding to formins and PI3P, causing either loss-of-function in actin assembly or gain-of-toxic function in autophagic/endo-lysosomal pathways, while in osteoclasts PFN1 specifically controls actin ring formation independent of NF-κB signaling."},"narrative":{"mechanistic_narrative":"PFN1 (profilin-1) is a small actin-binding protein that drives cytoskeletal remodeling by engaging monomeric actin and polyproline-motif partners such as VASP and formins, thereby promoting actin polymerization and processes that depend on it including cell migration, neuromuscular junction remodeling, and osteoclast actin-ring formation [PMID:30814249, PMID:28379367, PMID:40458045]. Its interaction with polyproline ligands is mediated through an alpha helix that simultaneously contacts actin and polyproline, and binding to VASP is gated by PKA-mediated phosphorylation at Ser137, which suppresses the interaction and contributes to the anti-migratory effects of cAMP/PKA signaling [PMID:34074767, PMID:30814249]. PFN1 abundance is tightly controlled by multiple ubiquitin-dependent routes: FBXL4 directs K48-linked ubiquitination at K70 to drive proteasomal turnover and preserve sarcomeric integrity in cardiomyocytes, SH3BGRL accelerates PFN1 degradation via the E3 ligase STUB1, and TRIM37-mediated K116 ubiquitination converts PFN1 into a recognition motif for the cargo receptor SQSTM1/p62 to enable selective autophagy [PMID:41589689, PMID:34331014, PMID:42260986]. ALS-linked mutations partition into distinct mechanisms: C71G is severely destabilized and aggregates, forming detergent-insoluble inclusions that seed pathology and sequester the chaperone DNAJB6, while M114T and G118V retain or augment formin-mediated actin assembly yet acquire toxic gains of function, including enhanced PI3P binding and dysregulation of autophagic and endo-lysosomal clearance [PMID:34074767, PMID:27681617, PMID:37817804, PMID:38509062, PMID:35628504]. Loss-of-function PFN1 variants cause a Paget's-disease-like osteoclast phenotype, where PFN1 specifically governs actin-ring formation independent of NF-κB signaling [PMID:32392277, PMID:40458045].","teleology":[{"year":2016,"claim":"Established that ALS-associated mutant PFN1 is causally pathogenic in vivo and that disease onset precedes aggregate accumulation, separating toxicity from inclusion formation.","evidence":"Transgenic mouse model expressing C71G vs wild-type PFN1 with histopathology and behavioral readouts","pmids":["27681617"],"confidence":"High","gaps":["Does not define the molecular trigger of degeneration preceding aggregation","Limited to the C71G variant"]},{"year":2017,"claim":"Defined wild-type PFN1's positive role in actin-dependent neuromuscular junction remodeling and showed ALS mutants are partial loss-of-function in this process.","evidence":"Drosophila transgenic model with NMJ morphology, F-actin, and locomotion assays","pmids":["28379367"],"confidence":"Medium","gaps":["Heterologous human-PFN1-in-fly system may not reflect mammalian neuron biology","Does not reconcile partial loss of function with gain-of-toxicity models"]},{"year":2019,"claim":"Identified PKA phosphorylation at Ser137 as a regulatory switch controlling the PFN1-VASP interaction and migration.","evidence":"Mutagenesis with knockdown-rescue, co-immunoprecipitation, and migration assays","pmids":["30814249"],"confidence":"High","gaps":["Does not establish the kinase-substrate stoichiometry in vivo","Effect on formin binding not addressed"]},{"year":2020,"claim":"Resolved the temporal order of PFN1 pathology, showing detergent-insoluble inclusions are the earliest detectable event in mutant rats, and identified a loss-of-function osteoclast disease mechanism for truncating PFN1 variants.","evidence":"C71G transgenic rats with temporal detergent fractionation; whole-exome sequencing plus osteoclastogenesis and murine knockdown for D107Rfs*3","pmids":["32754913","32392277"],"confidence":"Medium","gaps":["Aggregation-vs-onset ordering differs from the 2016 mouse study","Mechanism linking PFN1 loss to enhanced osteoclast actin-ring formation undefined"]},{"year":2021,"claim":"Distinguished the molecular fates of different ALS mutations, showing C71G is destabilized/loss-of-function while M114T and G118V retain altered formin binding and augmented actin assembly.","evidence":"Differential interactome proteomics, in vitro actin assembly, MD simulations, and cell-based expression","pmids":["34074767"],"confidence":"High","gaps":["Does not connect augmented actin assembly to neuronal toxicity","In vitro assembly may not capture cellular regulation"]},{"year":2021,"claim":"Showed PFN1 levels are controlled by E3-ligase-dependent degradation, with SH3BGRL promoting STUB1-mediated turnover and loss of PFN1 activating pro-metastatic signaling.","evidence":"Co-IP, protein degradation and translation assays, in vitro/in vivo tumor models","pmids":["34331014"],"confidence":"Medium","gaps":["Single lab; STUB1 ubiquitination site on PFN1 not mapped","Direct vs indirect ligase recruitment not fully resolved"]},{"year":2022,"claim":"Connected ALS mutant PFN1 to autophagy and mitochondrial quality control and identified additional regulators of PFN1 stability and signaling.","evidence":"Patient lymphoblasts/transgenic mice (M114T, RAB9 autophagy); lncRNA UCA1/USP14 Co-IP and ubiquitination (endothelial cells); Cdc42 Co-IP/MS signaling (satellite cells)","pmids":["35628504","36160709","36291059"],"confidence":"Medium","gaps":["These mechanisms are each from single labs and different cell systems","Whether they converge on a shared PFN1 regulatory node is unknown"]},{"year":2023,"claim":"Demonstrated prion-like seeding of PFN1 pathology and identified chaperone DNAJB6 sequestration as a consequence of pathogenic PFN1.","evidence":"Intramuscular seeding in transgenic rats plus DNAJB6 Co-IP","pmids":["37817804"],"confidence":"Medium","gaps":["Does not establish whether DNAJB6 sequestration drives toxicity","Seeding species/conformer not biochemically defined"]},{"year":2024,"claim":"Defined a gain-of-toxic-function for ALS mutant PFN1 in non-neuronal cells, with enhanced PI3P binding driving autophagy and phagocytosis defects rescuable by rapamycin.","evidence":"iPSC-derived microglia with phagocytosis, PI3P binding, lipidomics, and rapamycin rescue","pmids":["38509062"],"confidence":"High","gaps":["Mechanistic link between PI3P binding and lipid dysmetabolism not fully resolved","Relevance to motor neuron death not directly tested"]},{"year":2026,"claim":"Mapped two site-specific ubiquitination events controlling PFN1 fate: FBXL4-driven K48 ubiquitination at K70 for proteasomal turnover, and TRIM37-driven K116 ubiquitination targeting PFN1 to p62-mediated selective autophagy during viral restriction.","evidence":"Co-IP, ubiquitination site mapping, AAV in mouse hearts and hiPSC-cardiomyocytes (FBXL4/K70); KSHV replication and autophagy assays (TRIM37/K116)","pmids":["41589689","42260986"],"confidence":"Medium","gaps":["How K70 vs K116 ubiquitination is selected in different contexts is unclear","TRIM37/K116 mechanism is single-lab"]},{"year":null,"claim":"How PFN1's normal actin-regulatory activity, its multiple competing degradation routes, and the divergent loss- vs gain-of-function consequences of ALS mutations are mechanistically integrated within a single neuron remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling partial loss of actin function with autophagic gain-of-toxicity","Tissue-specific selection among FBXL4, STUB1, and TRIM37 degradation pathways undefined","Structural basis of mutation-specific PI3P binding not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,6,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,5,13]}],"complexes":[],"partners":["VASP","FBXL4","STUB1","TRIM37","SQSTM1","CDC42","DNAJB6","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07737","full_name":"Profilin-1","aliases":["Epididymis tissue protein Li 184a","Profilin I"],"length_aa":140,"mass_kda":15.1,"function":"Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P07737/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PFN1","classification":"Common Essential","n_dependent_lines":975,"n_total_lines":1208,"dependency_fraction":0.8071192052980133},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108518","cell_line_id":"CID000619","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"ACTG1","stoichiometry":10.0},{"gene":"RPS4X","stoichiometry":4.0},{"gene":"ACTR2","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"INPPL1","stoichiometry":0.2},{"gene":"CYFIP1","stoichiometry":0.2},{"gene":"NHSL1","stoichiometry":0.2},{"gene":"BRK1","stoichiometry":0.2},{"gene":"SOWAHC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000619","total_profiled":1310},"omim":[{"mim_id":"620475","title":"THROMBOCYTOPENIA 8, WITH DYSMORPHIC FEATURES AND DEVELOPMENTAL DELAY; THC8","url":"https://www.omim.org/entry/620475"},{"mim_id":"617861","title":"MYB-RELATED TRANSCRIPTION FACTOR, PARTNER OF PROFILIN; MYPOP","url":"https://www.omim.org/entry/617861"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"614808","title":"AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18","url":"https://www.omim.org/entry/614808"},{"mim_id":"612812","title":"PROFILIN 3; PFN3","url":"https://www.omim.org/entry/612812"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PFN1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P07737","domains":[{"cath_id":"3.30.450.30","chopping":"1-140","consensus_level":"medium","plddt":95.7254,"start":1,"end":140}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07737","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07737-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07737-F1-predicted_aligned_error_v6.png","plddt_mean":95.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PFN1","jax_strain_url":"https://www.jax.org/strain/search?query=PFN1"},"sequence":{"accession":"P07737","fasta_url":"https://rest.uniprot.org/uniprotkb/P07737.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07737/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07737"}},"corpus_meta":[{"pmid":"27681617","id":"PMC_27681617","title":"Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27681617","citation_count":89,"is_preprint":false},{"pmid":"15365097","id":"PMC_15365097","title":"The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15365097","citation_count":62,"is_preprint":false},{"pmid":"23428184","id":"PMC_23428184","title":"PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis.","date":"2013","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23428184","citation_count":54,"is_preprint":false},{"pmid":"31863778","id":"PMC_31863778","title":"HLA-F-AS1/miR-330-3p/PFN1 axis promotes colorectal cancer 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Molecular dynamics simulations revealed mutation-induced changes in internal dynamic couplings within an alpha helix of PFN1 that directly contacts both actin and polyproline. In contrast, C71G is more severely destabilized, resulting in reduced protein expression and loss-of-function in actin assembly.\",\n      \"method\": \"Unbiased proteomics (differential interactome), in vitro actin assembly assays, molecular dynamics simulations, cell-based expression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (proteomics, in vitro reconstitution, MD simulations, cell-based assays) in a single rigorous study\",\n      \"pmids\": [\"34074767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transgenic mice expressing ALS-associated mutant PFN1 (C71G), but not wild-type PFN1, develop progressive motor neuron loss, muscle weakness, and paralysis. Mutant PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM1 levels in motor neurons. Acceleration of motor neuron degeneration precedes accumulation of mutant PFN1 aggregates, indicating aggregation is not the trigger of disease onset.\",\n      \"method\": \"Transgenic mouse model (gain-of-function), histopathology, immunostaining, behavioral testing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-controlled transgenic mouse model with multiple phenotypic readouts, replicated across multiple lines\",\n      \"pmids\": [\"27681617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PFN1 interaction with VASP is promoted by cell-substrate adhesion and requires downregulation of PKA activity. PKA-mediated phosphorylation of PFN1 at Ser137 negatively regulates the PFN1-VASP interaction and contributes to anti-migratory effects of cAMP/PKA agonists.\",\n      \"method\": \"Mutagenesis in overexpression and knockdown-rescue settings, co-immunoprecipitation, cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with knockdown-rescue and functional cell migration assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30814249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALS-linked mutant PFN1 (G118V, M114T, C71G) expressed in iPSC-derived microglia causes lipid dysmetabolism, autophagy dysregulation, and deficient phagocytosis. Mutant PFN1 exhibits enhanced binding affinity for PI3P (a signaling molecule in autophagic/endocytic processing). Rapamycin rescued phagocytic dysfunction, implicating a gain-of-toxic function in autophagic and endo-lysosomal pathways.\",\n      \"method\": \"iPSC-derived microglia (iMGs), phagocytosis assays, PI3P binding assays, rapamycin rescue experiments, lipidomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC-derived cell model with multiple orthogonal functional assays and pharmacological rescue in a peer-reviewed study\",\n      \"pmids\": [\"38509062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The lncRNA UCA1 physically binds USP14 (a deubiquitinating enzyme) and functions as a scaffold to recruit USP14 to PFN1, inhibiting ubiquitination-dependent degradation of PFN1 and prolonging its half-life, thereby activating the RhoA/ROCK pathway and inducing ROS production in endothelial cells.\",\n      \"method\": \"Coculture system, exosome extraction, co-immunoprecipitation, ubiquitination assays, ROS measurement\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mechanistic Co-IP and ubiquitination assays in a single lab, multiple methods but not independently replicated\",\n      \"pmids\": [\"36160709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SH3BGRL promotes degradation of PFN1 by accelerating translation of the E3 ubiquitin ligase STUB1 (via interaction with ribosomal proteins) and/or enhancing the interaction of PFN1 with STUB1, leading to proteasomal degradation of PFN1. Loss of PFN1 activates AKT, NF-kB, and WNT signaling pathways, while forced PFN1 expression neutralizes SH3BGRL-induced metastasis with PTEN upregulation and PI3K-AKT inactivation.\",\n      \"method\": \"Co-immunoprecipitation, protein degradation assays, ribosome interaction studies, in vitro and in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple mechanistic assays (Co-IP, translation assays, rescue experiments, in vivo) in single lab\",\n      \"pmids\": [\"34331014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PFN1 mutation M114T destabilizes the protein and deregulates the RAB9-mediated alternative autophagy pathway involved in clearance of damaged mitochondria. Motor neurons expressing M114T mutant PFN1 show mitochondrial abnormalities in vivo.\",\n      \"method\": \"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy pathway marker analysis, mitochondrial morphology assessment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells plus in vivo model, multiple readouts but single lab\",\n      \"pmids\": [\"35628504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In a Drosophila model, expression of wild-type human PFN1 in motor neurons increases ghost boutons, active zone density, F-actin content, and filopodia formation at larval NMJs. ALS-causative PFN1 mutants display less pronounced NMJ phenotypes, suggesting partial loss of function in promoting NMJ remodeling and actin polymerization.\",\n      \"method\": \"Drosophila transgenic model, NMJ morphology analysis, locomotion and lifespan assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila model with quantitative morphological and functional readouts, single lab\",\n      \"pmids\": [\"28379367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A frameshift mutation (D107Rfs*3) in PFN1 causing truncation of the C-terminal portion of the protein leads to a loss of function of profilin 1 activity. In vitro osteoclastogenesis from mutation carriers showed higher numbers of osteoclasts with PDB-like features, and PFN1 silencing in murine bone marrow-derived monocytes recapitulated the phenotype, suggesting enhanced osteoclast motility and actin ring formation.\",\n      \"method\": \"Whole exome sequencing, in vitro osteoclastogenesis from PBMCs, PFN1 silencing in murine bone marrow-derived monocytes\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — patient-derived functional assays plus murine knockdown model, single lab, two orthogonal approaches\",\n      \"pmids\": [\"32392277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PFN1 inhibits myogenic differentiation of bovine skeletal muscle satellite cells via binding to Cdc42 (identified by co-immunoprecipitation and mass spectrometry). PFN1 activates Cdc42, which increases phosphorylation of PAK, which in turn activates JNK phosphorylation, and both PAK and JNK are inhibitors of myogenic differentiation.\",\n      \"method\": \"Immunoprecipitation combined with mass spectrometry, kinase phosphorylation assays, overexpression/knockdown experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP/MS to identify binding partner plus signaling cascade verification, single lab\",\n      \"pmids\": [\"36291059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Detergent-insoluble PFN1 inclusions are the first detected pathology in otherwise asymptomatic transgenic rats expressing mutant human PFN1 (C71G), preceding motor neuron loss and muscle atrophy, suggesting protein aggregation is involved in the neurodegeneration.\",\n      \"method\": \"Human genomic DNA transgenic rats, detergent fractionation, histopathology, behavioral testing\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic transgenic rat model with careful temporal analysis, single lab\",\n      \"pmids\": [\"32754913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intramuscular administration of detergent-insoluble materials from paralyzed mutant PFN1 transgenic rats accelerated development of PFN1 inclusions and ALS-like phenotypes in asymptomatic recipient mutant PFN1 rats (seeding effect). Pathogenic PFN1 exhibited enhanced affinity for molecular chaperone DNAJB6, leading to sequestration of DNAJB6 within protein inclusions.\",\n      \"method\": \"Intrinsic seeding experiment in transgenic rats, detergent fractionation, co-immunoprecipitation for DNAJB6 interaction\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo seeding experiment with appropriate controls plus binding assay, single lab\",\n      \"pmids\": [\"37817804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXL4 (an F-box protein) interacts with PFN1 and promotes K48-linked ubiquitination of PFN1 at lysine 70, leading to its proteasomal degradation and preservation of sarcomeric integrity in cardiomyocytes. Loss of FBXL4 leads to PFN1 accumulation and cardiac dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping (K70), AAV-mediated knockdown/overexpression in mouse hearts, hiPSC-derived cardiomyocytes\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific ubiquitination mapping at K70, multiple in vivo and in vitro models, AAV rescue experiments, hiPSC validation\",\n      \"pmids\": [\"41589689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PFN1 interacts with KSHV helicase ORF44, and the E3 ubiquitin ligase TRIM37 facilitates polyubiquitination of PFN1 at lysine 116. This ubiquitinated PFN1 serves as a recognition motif for the cargo receptor SQSTM1/p62, leading to autophagic degradation of ORF44 and inhibition of KSHV lytic replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping (K116), autophagy-lysosomal degradation assays, KSHV replication assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic Co-IP, site-specific ubiquitination mapping, functional viral replication assays, single lab\",\n      \"pmids\": [\"42260986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A PFN1 L112P mutation in osteoclasts leads to enhanced actin ring-like structures at bone surfaces without affecting NF-κB activation, suggesting a specific role of PFN1 in actin ring formation during osteoclast function independent of NF-κB signaling.\",\n      \"method\": \"Heterozygous knock-in mouse model (Pfn1 L112P), osteoclast culture, immunofluorescence for actin rings, NF-κB activation assays\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with specific cellular readouts, single lab\",\n      \"pmids\": [\"40458045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oleic acid increases acetylation of PFN1 and promotes prostate cancer cell migration/invasion with enhanced PFN1 and FLNA localization to the leading edge. EPA decreases PFN1 acetylation and impedes lamellipodia/filopodia formation by reducing PFN1 localization to the leading edge.\",\n      \"method\": \"Global acetylome profiling, immunofluorescence, cell migration/invasion assays\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — acetylome profiling with single immunofluorescence readout, no direct mutagenesis of acetylation sites, single lab\",\n      \"pmids\": [\"38430206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Computational and simulation analysis of the PFN1–polyproline-10 binding interface confirmed that residues W3, H133, and S137 of PFN1 form favorable hydrogen bonds with polyproline-10, consistent with crystallographic binding structures and suggesting a zipping process during binding.\",\n      \"method\": \"Umbrella sampling (PMF), molecular dynamics simulations, steered molecular dynamics\",\n      \"journal\": \"The Journal of chemical physics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational only, no experimental validation of specific residue mutations in this paper\",\n      \"pmids\": [\"30621420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nicotine induces PFN1 overexpression in mouse elongated spermatids via hypomethylation of the Pfn1 promoter, leading to increased actin polymerization and elevated sperm motility.\",\n      \"method\": \"2D gel electrophoresis, mass spectrometry, bisulfite sequencing (promoter methylation), sperm motility analysis\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative promoter methylation analysis without direct functional rescue experiments linking Pfn1 overexpression to motility\",\n      \"pmids\": [\"26311342\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PFN1 (profilin-1) is a small actin-binding protein that promotes formin-mediated actin polymerization and regulates cytoskeletal dynamics by binding monomeric actin and polyproline-motif-containing proteins (such as VASP and formins); its activity is post-translationally regulated by PKA-mediated phosphorylation at Ser137 (inhibiting VASP interaction), K48-linked ubiquitination at K70 by FBXL4 (promoting proteasomal degradation), and K116 ubiquitination by TRIM37 (enabling SQSTM1/p62-mediated selective autophagy); ALS-linked mutations (C71G, M114T, G118V) destabilize the protein or alter its binding to formins and PI3P, causing either loss-of-function in actin assembly or gain-of-toxic function in autophagic/endo-lysosomal pathways, while in osteoclasts PFN1 specifically controls actin ring formation independent of NF-κB signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PFN1 (profilin-1) is a small actin-binding protein that drives cytoskeletal remodeling by engaging monomeric actin and polyproline-motif partners such as VASP and formins, thereby promoting actin polymerization and processes that depend on it including cell migration, neuromuscular junction remodeling, and osteoclast actin-ring formation [#2, #7, #14]. Its interaction with polyproline ligands is mediated through an alpha helix that simultaneously contacts actin and polyproline, and binding to VASP is gated by PKA-mediated phosphorylation at Ser137, which suppresses the interaction and contributes to the anti-migratory effects of cAMP/PKA signaling [#0, #2]. PFN1 abundance is tightly controlled by multiple ubiquitin-dependent routes: FBXL4 directs K48-linked ubiquitination at K70 to drive proteasomal turnover and preserve sarcomeric integrity in cardiomyocytes, SH3BGRL accelerates PFN1 degradation via the E3 ligase STUB1, and TRIM37-mediated K116 ubiquitination converts PFN1 into a recognition motif for the cargo receptor SQSTM1/p62 to enable selective autophagy [#12, #5, #13]. ALS-linked mutations partition into distinct mechanisms: C71G is severely destabilized and aggregates, forming detergent-insoluble inclusions that seed pathology and sequester the chaperone DNAJB6, while M114T and G118V retain or augment formin-mediated actin assembly yet acquire toxic gains of function, including enhanced PI3P binding and dysregulation of autophagic and endo-lysosomal clearance [#0, #1, #11, #3, #6]. Loss-of-function PFN1 variants cause a Paget's-disease-like osteoclast phenotype, where PFN1 specifically governs actin-ring formation independent of NF-\\u03baB signaling [#8, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that ALS-associated mutant PFN1 is causally pathogenic in vivo and that disease onset precedes aggregate accumulation, separating toxicity from inclusion formation.\",\n      \"evidence\": \"Transgenic mouse model expressing C71G vs wild-type PFN1 with histopathology and behavioral readouts\",\n      \"pmids\": [\"27681617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the molecular trigger of degeneration preceding aggregation\", \"Limited to the C71G variant\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined wild-type PFN1's positive role in actin-dependent neuromuscular junction remodeling and showed ALS mutants are partial loss-of-function in this process.\",\n      \"evidence\": \"Drosophila transgenic model with NMJ morphology, F-actin, and locomotion assays\",\n      \"pmids\": [\"28379367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous human-PFN1-in-fly system may not reflect mammalian neuron biology\", \"Does not reconcile partial loss of function with gain-of-toxicity models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified PKA phosphorylation at Ser137 as a regulatory switch controlling the PFN1-VASP interaction and migration.\",\n      \"evidence\": \"Mutagenesis with knockdown-rescue, co-immunoprecipitation, and migration assays\",\n      \"pmids\": [\"30814249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the kinase-substrate stoichiometry in vivo\", \"Effect on formin binding not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the temporal order of PFN1 pathology, showing detergent-insoluble inclusions are the earliest detectable event in mutant rats, and identified a loss-of-function osteoclast disease mechanism for truncating PFN1 variants.\",\n      \"evidence\": \"C71G transgenic rats with temporal detergent fractionation; whole-exome sequencing plus osteoclastogenesis and murine knockdown for D107Rfs*3\",\n      \"pmids\": [\"32754913\", \"32392277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Aggregation-vs-onset ordering differs from the 2016 mouse study\", \"Mechanism linking PFN1 loss to enhanced osteoclast actin-ring formation undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished the molecular fates of different ALS mutations, showing C71G is destabilized/loss-of-function while M114T and G118V retain altered formin binding and augmented actin assembly.\",\n      \"evidence\": \"Differential interactome proteomics, in vitro actin assembly, MD simulations, and cell-based expression\",\n      \"pmids\": [\"34074767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not connect augmented actin assembly to neuronal toxicity\", \"In vitro assembly may not capture cellular regulation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PFN1 levels are controlled by E3-ligase-dependent degradation, with SH3BGRL promoting STUB1-mediated turnover and loss of PFN1 activating pro-metastatic signaling.\",\n      \"evidence\": \"Co-IP, protein degradation and translation assays, in vitro/in vivo tumor models\",\n      \"pmids\": [\"34331014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; STUB1 ubiquitination site on PFN1 not mapped\", \"Direct vs indirect ligase recruitment not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ALS mutant PFN1 to autophagy and mitochondrial quality control and identified additional regulators of PFN1 stability and signaling.\",\n      \"evidence\": \"Patient lymphoblasts/transgenic mice (M114T, RAB9 autophagy); lncRNA UCA1/USP14 Co-IP and ubiquitination (endothelial cells); Cdc42 Co-IP/MS signaling (satellite cells)\",\n      \"pmids\": [\"35628504\", \"36160709\", \"36291059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These mechanisms are each from single labs and different cell systems\", \"Whether they converge on a shared PFN1 regulatory node is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated prion-like seeding of PFN1 pathology and identified chaperone DNAJB6 sequestration as a consequence of pathogenic PFN1.\",\n      \"evidence\": \"Intramuscular seeding in transgenic rats plus DNAJB6 Co-IP\",\n      \"pmids\": [\"37817804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether DNAJB6 sequestration drives toxicity\", \"Seeding species/conformer not biochemically defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a gain-of-toxic-function for ALS mutant PFN1 in non-neuronal cells, with enhanced PI3P binding driving autophagy and phagocytosis defects rescuable by rapamycin.\",\n      \"evidence\": \"iPSC-derived microglia with phagocytosis, PI3P binding, lipidomics, and rapamycin rescue\",\n      \"pmids\": [\"38509062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between PI3P binding and lipid dysmetabolism not fully resolved\", \"Relevance to motor neuron death not directly tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped two site-specific ubiquitination events controlling PFN1 fate: FBXL4-driven K48 ubiquitination at K70 for proteasomal turnover, and TRIM37-driven K116 ubiquitination targeting PFN1 to p62-mediated selective autophagy during viral restriction.\",\n      \"evidence\": \"Co-IP, ubiquitination site mapping, AAV in mouse hearts and hiPSC-cardiomyocytes (FBXL4/K70); KSHV replication and autophagy assays (TRIM37/K116)\",\n      \"pmids\": [\"41589689\", \"42260986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K70 vs K116 ubiquitination is selected in different contexts is unclear\", \"TRIM37/K116 mechanism is single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PFN1's normal actin-regulatory activity, its multiple competing degradation routes, and the divergent loss- vs gain-of-function consequences of ALS mutations are mechanistically integrated within a single neuron remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling partial loss of actin function with autophagic gain-of-toxicity\", \"Tissue-specific selection among FBXL4, STUB1, and TRIM37 degradation pathways undefined\", \"Structural basis of mutation-specific PI3P binding not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 6, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 5, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VASP\", \"FBXL4\", \"STUB1\", \"TRIM37\", \"SQSTM1\", \"CDC42\", \"DNAJB6\", \"USP14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}