{"gene":"ELMOD2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2007,"finding":"ELMOD2 was purified from bovine testis and identified as a GTPase-activating protein (GAP) for ARL2. It also exhibited GAP activity against ARF proteins despite lacking the canonical ARF GAP sequence signature, demonstrating unusually broad specificity within the ARF family.","method":"Protein purification from bovine testis, in vitro GAP activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical purification and in vitro enzymatic assay establishing GAP activity; single lab but two substrates tested with direct assays","pmids":["17452337"],"is_preprint":false},{"year":2009,"finding":"ELMOD2 is required for TLR3-dependent type I and type III interferon expression in human alveolar epithelial cells and macrophages. Forced overexpression of ELMOD2 increased IFN mRNA levels, while siRNA knockdown inhibited antiviral cytokine expression upon TLR3 activation.","method":"Overexpression cell model (A549), siRNA knockdown, expression microarray, qPCR, TLR3 activation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (overexpression, knockdown, pathway activation) in one study; single lab","pmids":["19966137"],"is_preprint":false},{"year":2015,"finding":"ELMOD2 is anchored to lipid droplets (LDs) via palmitoylation and regulates ATGL (adipocyte triglyceride lipase) recruitment to LDs. Knockdown of ELMOD2 increased ATGL on LDs and decreased total cellular triglycerides; rescue required both GAP activity and palmitoylation-dependent LD localization.","method":"siRNA knockdown, site-directed mutagenesis (GAP-dead and palmitoylation-deficient mutants), triglyceride quantification, rescue with siRNA-resistant constructs","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of active site and palmitoylation site with functional rescue; multiple orthogonal methods in one study; single lab","pmids":["25904333"],"is_preprint":false},{"year":2015,"finding":"ELMOD2 localizes to lipid droplets, endoplasmic reticulum, and mitochondria. Palmitoylation is specifically required for its distribution to lipid droplets, while LD-deficient palmitoylation mutant fails to reconstitute ATGL transport after ELMOD2 knockdown.","method":"Immunofluorescence, palmitoylation-deficient mutagenesis, subcellular fractionation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with mutagenesis tied to functional consequence; single lab","pmids":["25904333"],"is_preprint":false},{"year":2017,"finding":"ELMOD2 co-localizes with ARL2 in mouse oocytes and physically interacts with ARL2 (co-immunoprecipitation). ELMOD2 knockdown causes mitochondrial aggregation, reduced ATP levels, meiotic delay, abnormal chromosomal segregation, and aneuploidy, implicating ELMOD2-ARL2 interaction in maintaining mitochondrial dynamics required for meiotic progression.","method":"siRNA knockdown in mouse oocytes, co-immunoprecipitation, immunofluorescence co-localization, ATP measurement, polar body extrusion assay, chromosome spread analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown with multiple phenotypic readouts; single lab","pmids":["28324667"],"is_preprint":false},{"year":2019,"finding":"ELMOD2 acts downstream of ARL2 to promote mitochondrial fusion in a mitofusin-dependent manner. Loss of ELMOD2 causes mitochondrial fragmentation and reduced fusion rate; overexpression promotes tubulation and increases fusion rate. A GAP-dead mutant of ELMOD2 retains the ability to promote fusion, indicating GAP activity is dispensable for this function. ELMOD2, ARL2, MFN1/2, MIRO1/2, and mitoPLD co-localize at discrete puncta along mitochondria.","method":"CRISPR/gene knockout, overexpression, GAP-dead mutagenesis, mitochondrial morphology assay, fusion rate measurement (photoactivatable GFP), immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO, GAP-dead mutagenesis, quantitative fusion assay, and co-localization; multiple orthogonal methods; single lab","pmids":["30865555"],"is_preprint":false},{"year":2020,"finding":"ELMOD2 acts with ARL2 and TBCD to support microtubule nucleation from centrosomes, and separately acts with ARF6 in cytokinesis. These two functions are separable and linked to distinct GTPase partners, demonstrating that ELMOD2 can serve as both a GAP and an effector for different ARF family GTPases at different cellular locations.","method":"ELMOD2 deletion in mouse embryonic fibroblasts (MEFs), rescue with ELMOD2-myc expression, microtubule nucleation assay, cytokinesis analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with functional rescue, multiple pathways and GTPases defined; single lab","pmids":["32614697"],"is_preprint":false},{"year":2021,"finding":"ELMOD2 acts in a common pathway with ARL2 and Rootletin to suppress spurious ciliation, maintain centrosome cohesion, and regulate ciliary vesicle docking. Mechanistically, ELMOD2-KO MEFs show increased ciliation, multiciliation, centrin accumulation inside cilia, and loss of rootlets. Epistasis experiments place ELMOD2, Rootletin, and ARL2 downstream of TTBK2 and upstream of CP110. Increasing ARL2 activity or overexpressing Rootletin rescued ELMOD2-deletion phenotypes; deletion of Rootletin yielded similar phenotypes rescued by increasing ARL2 but not ELMOD2 overexpression.","method":"ELMOD2 deletion (MEFs), Rootletin deletion, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, immunofluorescence, ciliary marker analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple rescue conditions and pathway placement; multiple orthogonal approaches; single lab","pmids":["33596093"],"is_preprint":false}],"current_model":"ELMOD2 is a broadly-active ARF family GTPase-activating protein (GAP) with established roles in multiple cellular processes: it acts downstream of ARL2 (and can function independently of its GAP activity) to promote mitochondrial fusion in a mitofusin-dependent manner, suppresses spurious ciliation and maintains centrosome cohesion with ARL2 and Rootletin, supports centrosomal microtubule nucleation with ARL2/TBCD, regulates ATGL recruitment to lipid droplets via palmitoylation-dependent LD localization and Arf1-COPI modulation, participates in ARF6-dependent cytokinesis, and is required for TLR3-dependent antiviral interferon responses."},"narrative":{"mechanistic_narrative":"ELMOD2 is a broadly-specific ARF-family GTPase-activating protein (GAP) that coordinates membrane and cytoskeletal dynamics across multiple organelles by acting both as a GAP and as a GTPase effector [PMID:17452337]. It was first purified as a GAP for ARL2 that, unusually, also accelerates GTP hydrolysis on ARF proteins despite lacking the canonical ARF-GAP signature, defining an exceptionally broad ARF-family specificity [PMID:17452337]. Working downstream of ARL2, ELMOD2 promotes mitofusin-dependent mitochondrial fusion, with ELMOD2, ARL2, MFN1/2, MIRO1/2 and mitoPLD co-localizing at discrete mitochondrial puncta; this fusion-promoting function is retained by a GAP-dead mutant, showing it is GAP-independent [PMID:30865555], and ELMOD2-ARL2 interaction supports the mitochondrial dynamics required for meiotic progression [PMID:28324667]. With ARL2 and Rootletin it suppresses spurious ciliation, maintains centrosome cohesion and regulates ciliary vesicle docking, functioning downstream of TTBK2 and upstream of CP110 [PMID:33596093], and with ARL2/TBCD it supports centrosomal microtubule nucleation while separately acting with ARF6 in cytokinesis [PMID:32614697]. At lipid droplets, ELMOD2 is anchored by palmitoylation and limits ATGL recruitment, with both its GAP activity and palmitoylation-dependent localization required to control cellular triglyceride levels [PMID:25904333]. ELMOD2 is also required for TLR3-dependent type I and III interferon expression in antiviral responses [PMID:19966137].","teleology":[{"year":2007,"claim":"Establishing the core biochemical activity: ELMOD2 was identified as a GAP for ARL2 that also acts on ARF proteins, defining it as a broad-specificity ARF-family GAP and the molecular basis for its later roles.","evidence":"Protein purification from bovine testis and in vitro GAP assays against ARL2 and ARF substrates","pmids":["17452337"],"confidence":"High","gaps":["No structural basis for the broad specificity despite lacking the canonical ARF-GAP signature","Cellular substrates and physiological contexts not addressed","No partners beyond the tested GTPases identified"]},{"year":2009,"claim":"First cellular role linked ELMOD2 to innate immunity, showing it is required for TLR3-driven antiviral interferon expression.","evidence":"Overexpression and siRNA knockdown in A549 cells and macrophages with microarray, qPCR, and TLR3 activation readouts","pmids":["19966137"],"confidence":"Medium","gaps":["Molecular step in the TLR3 pathway connecting GAP activity to IFN induction not defined","Whether GAP activity or a specific GTPase partner is required not tested","Single lab, single cell-type panel"]},{"year":2015,"claim":"Defined a lipid-droplet function and the determinants required for it, showing ELMOD2 controls ATGL recruitment and triglyceride levels via palmitoylation-dependent LD localization and GAP activity.","evidence":"siRNA knockdown, GAP-dead and palmitoylation-deficient mutagenesis with siRNA-resistant rescue, triglyceride quantification, immunofluorescence, fractionation","pmids":["25904333"],"confidence":"High","gaps":["The relevant GTPase substrate at lipid droplets not identified in this work","Palmitoylation enzyme(s) acting on ELMOD2 unknown","Mechanism connecting ELMOD2 to Arf1-COPI not directly demonstrated here"]},{"year":2017,"claim":"Tied ELMOD2 physically and functionally to ARL2 in mitochondrial dynamics, showing the interaction is required for meiotic progression.","evidence":"Co-immunoprecipitation, co-localization, siRNA knockdown in mouse oocytes with ATP, polar body, and chromosome readouts","pmids":["28324667"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal or endogenous validation","Direct molecular mechanism linking ARL2 interaction to mitochondrial morphology not resolved","Whether GAP activity is required for the oocyte phenotype untested"]},{"year":2019,"claim":"Resolved the mechanism of ELMOD2 in mitochondrial fusion, showing it acts downstream of ARL2 to promote mitofusin-dependent fusion independently of its GAP activity.","evidence":"CRISPR knockout, overexpression, GAP-dead mutagenesis, photoactivatable-GFP fusion-rate assays, and co-localization with ARL2/MFN1/2/MIRO1/2/mitoPLD","pmids":["30865555"],"confidence":"High","gaps":["The non-catalytic (effector) mechanism by which ELMOD2 promotes fusion not defined","Direct interactions with mitofusins or MIRO proteins not established","Relationship of the fusion role to the lipid-droplet/ER localization unclear"]},{"year":2020,"claim":"Demonstrated functional versatility by separating two centrosome/cytokinesis roles tied to distinct GTPase partners (ARL2/TBCD for microtubule nucleation; ARF6 for cytokinesis).","evidence":"ELMOD2 deletion in MEFs with myc-tagged rescue, microtubule nucleation and cytokinesis assays","pmids":["32614697"],"confidence":"Medium","gaps":["Whether ELMOD2 acts as GAP or effector in each role not fully delineated","Direct physical interaction with ARF6 and TBCD not biochemically mapped here","Spatial regulation directing ELMOD2 to distinct partners unknown"]},{"year":2021,"claim":"Placed ELMOD2 in a defined ciliation-control pathway, showing it acts with ARL2 and Rootletin to suppress spurious ciliation and maintain centrosome cohesion within a TTBK2-to-CP110 axis.","evidence":"ELMOD2 and Rootletin deletion in MEFs, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, ciliary marker immunofluorescence","pmids":["33596093"],"confidence":"High","gaps":["Direct biochemical interaction among ELMOD2, ARL2, and Rootletin not shown","How ELMOD2 GAP activity feeds into Rootletin/rootlet maintenance unresolved","Mechanistic link to ciliary vesicle docking not detailed"]},{"year":null,"claim":"How a single broad-specificity GAP is partitioned among mitochondria, lipid droplets, centrosomes, and immune signaling—and when it acts catalytically versus as a non-catalytic effector—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model for spatial/partner selection across organelles","Catalytic versus effector contributions not systematically separated across functions","No structural data explaining broad ARF-family specificity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]}],"complexes":[],"partners":["ARL2","ARF6","TBCD","ROOTLETIN","MFN1","MFN2","ATGL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZ81","full_name":"ELMO domain-containing protein 2","aliases":[],"length_aa":293,"mass_kda":35.0,"function":"Acts as a GTPase-activating protein (GAP) toward guanine nucleotide exchange factors like ARL2, ARL3, ARF1 and ARF6, but not for GTPases outside the Arf family. Regulates IFN-related antiviral responses","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8IZ81/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELMOD2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ELMOD2","total_profiled":1310},"omim":[{"mim_id":"615456","title":"ELMO/CED12 DOMAIN-CONTAINING PROTEIN 1; ELMOD1","url":"https://www.omim.org/entry/615456"},{"mim_id":"615427","title":"ELMO/CED12 DOMAIN-CONTAINING PROTEIN 3; ELMOD3","url":"https://www.omim.org/entry/615427"},{"mim_id":"610310","title":"MGAT4 FAMILY, MEMBER D; MGAT4D","url":"https://www.omim.org/entry/610310"},{"mim_id":"610196","title":"ELMO/CED12 DOMAIN-CONTAINING PROTEIN 2; ELMOD2","url":"https://www.omim.org/entry/610196"},{"mim_id":"601175","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 2; ARL2","url":"https://www.omim.org/entry/601175"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELMOD2"},"hgnc":{"alias_symbol":["MGC10084"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZ81","domains":[{"cath_id":"-","chopping":"2-117","consensus_level":"high","plddt":91.1984,"start":2,"end":117},{"cath_id":"-","chopping":"123-284","consensus_level":"high","plddt":97.2306,"start":123,"end":284}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZ81","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZ81-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZ81-F1-predicted_aligned_error_v6.png","plddt_mean":94.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELMOD2","jax_strain_url":"https://www.jax.org/strain/search?query=ELMOD2"},"sequence":{"accession":"Q8IZ81","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZ81.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZ81/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZ81"}},"corpus_meta":[{"pmid":"16773575","id":"PMC_16773575","title":"ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.","date":"2006","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16773575","citation_count":82,"is_preprint":false},{"pmid":"17452337","id":"PMC_17452337","title":"ELMOD2 is an Arl2 GTPase-activating protein that also acts on Arfs.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17452337","citation_count":74,"is_preprint":false},{"pmid":"19966137","id":"PMC_19966137","title":"ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19966137","citation_count":50,"is_preprint":false},{"pmid":"25904333","id":"PMC_25904333","title":"ELMOD2 is anchored to lipid droplets by palmitoylation and regulates adipocyte triglyceride lipase recruitment.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25904333","citation_count":44,"is_preprint":false},{"pmid":"30865555","id":"PMC_30865555","title":"ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2.","date":"2019","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/30865555","citation_count":19,"is_preprint":false},{"pmid":"33596093","id":"PMC_33596093","title":"Roles for ELMOD2 and Rootletin in ciliogenesis.","date":"2021","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/33596093","citation_count":17,"is_preprint":false},{"pmid":"32614697","id":"PMC_32614697","title":"The ARF GAP ELMOD2 acts with different GTPases to regulate centrosomal microtubule nucleation and cytokinesis.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32614697","citation_count":13,"is_preprint":false},{"pmid":"28324667","id":"PMC_28324667","title":"GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes.","date":"2017","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28324667","citation_count":7,"is_preprint":false},{"pmid":"32982309","id":"PMC_32982309","title":"lncRNA CRNDE is Upregulated in Glioblastoma Multiforme and Facilitates Cancer Progression Through Targeting miR-337-3p and ELMOD2 Axis.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32982309","citation_count":5,"is_preprint":false},{"pmid":"40397299","id":"PMC_40397299","title":"ELMOD2 Overexpression Predicts Adverse Outcomes and Regulates Tumor Progression in Gliomas.","date":"2025","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/40397299","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6939,"output_tokens":2176,"usd":0.026728,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9258,"output_tokens":3251,"usd":0.063783,"stage2_stop_reason":"end_turn"},"total_usd":0.090511,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"ELMOD2 was purified from bovine testis and identified as a GTPase-activating protein (GAP) for ARL2. It also exhibited GAP activity against ARF proteins despite lacking the canonical ARF GAP sequence signature, demonstrating unusually broad specificity within the ARF family.\",\n      \"method\": \"Protein purification from bovine testis, in vitro GAP activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical purification and in vitro enzymatic assay establishing GAP activity; single lab but two substrates tested with direct assays\",\n      \"pmids\": [\"17452337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ELMOD2 is required for TLR3-dependent type I and type III interferon expression in human alveolar epithelial cells and macrophages. Forced overexpression of ELMOD2 increased IFN mRNA levels, while siRNA knockdown inhibited antiviral cytokine expression upon TLR3 activation.\",\n      \"method\": \"Overexpression cell model (A549), siRNA knockdown, expression microarray, qPCR, TLR3 activation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (overexpression, knockdown, pathway activation) in one study; single lab\",\n      \"pmids\": [\"19966137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELMOD2 is anchored to lipid droplets (LDs) via palmitoylation and regulates ATGL (adipocyte triglyceride lipase) recruitment to LDs. Knockdown of ELMOD2 increased ATGL on LDs and decreased total cellular triglycerides; rescue required both GAP activity and palmitoylation-dependent LD localization.\",\n      \"method\": \"siRNA knockdown, site-directed mutagenesis (GAP-dead and palmitoylation-deficient mutants), triglyceride quantification, rescue with siRNA-resistant constructs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of active site and palmitoylation site with functional rescue; multiple orthogonal methods in one study; single lab\",\n      \"pmids\": [\"25904333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELMOD2 localizes to lipid droplets, endoplasmic reticulum, and mitochondria. Palmitoylation is specifically required for its distribution to lipid droplets, while LD-deficient palmitoylation mutant fails to reconstitute ATGL transport after ELMOD2 knockdown.\",\n      \"method\": \"Immunofluorescence, palmitoylation-deficient mutagenesis, subcellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with mutagenesis tied to functional consequence; single lab\",\n      \"pmids\": [\"25904333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ELMOD2 co-localizes with ARL2 in mouse oocytes and physically interacts with ARL2 (co-immunoprecipitation). ELMOD2 knockdown causes mitochondrial aggregation, reduced ATP levels, meiotic delay, abnormal chromosomal segregation, and aneuploidy, implicating ELMOD2-ARL2 interaction in maintaining mitochondrial dynamics required for meiotic progression.\",\n      \"method\": \"siRNA knockdown in mouse oocytes, co-immunoprecipitation, immunofluorescence co-localization, ATP measurement, polar body extrusion assay, chromosome spread analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"28324667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELMOD2 acts downstream of ARL2 to promote mitochondrial fusion in a mitofusin-dependent manner. Loss of ELMOD2 causes mitochondrial fragmentation and reduced fusion rate; overexpression promotes tubulation and increases fusion rate. A GAP-dead mutant of ELMOD2 retains the ability to promote fusion, indicating GAP activity is dispensable for this function. ELMOD2, ARL2, MFN1/2, MIRO1/2, and mitoPLD co-localize at discrete puncta along mitochondria.\",\n      \"method\": \"CRISPR/gene knockout, overexpression, GAP-dead mutagenesis, mitochondrial morphology assay, fusion rate measurement (photoactivatable GFP), immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, GAP-dead mutagenesis, quantitative fusion assay, and co-localization; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"30865555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ELMOD2 acts with ARL2 and TBCD to support microtubule nucleation from centrosomes, and separately acts with ARF6 in cytokinesis. These two functions are separable and linked to distinct GTPase partners, demonstrating that ELMOD2 can serve as both a GAP and an effector for different ARF family GTPases at different cellular locations.\",\n      \"method\": \"ELMOD2 deletion in mouse embryonic fibroblasts (MEFs), rescue with ELMOD2-myc expression, microtubule nucleation assay, cytokinesis analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with functional rescue, multiple pathways and GTPases defined; single lab\",\n      \"pmids\": [\"32614697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELMOD2 acts in a common pathway with ARL2 and Rootletin to suppress spurious ciliation, maintain centrosome cohesion, and regulate ciliary vesicle docking. Mechanistically, ELMOD2-KO MEFs show increased ciliation, multiciliation, centrin accumulation inside cilia, and loss of rootlets. Epistasis experiments place ELMOD2, Rootletin, and ARL2 downstream of TTBK2 and upstream of CP110. Increasing ARL2 activity or overexpressing Rootletin rescued ELMOD2-deletion phenotypes; deletion of Rootletin yielded similar phenotypes rescued by increasing ARL2 but not ELMOD2 overexpression.\",\n      \"method\": \"ELMOD2 deletion (MEFs), Rootletin deletion, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, immunofluorescence, ciliary marker analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple rescue conditions and pathway placement; multiple orthogonal approaches; single lab\",\n      \"pmids\": [\"33596093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELMOD2 is a broadly-active ARF family GTPase-activating protein (GAP) with established roles in multiple cellular processes: it acts downstream of ARL2 (and can function independently of its GAP activity) to promote mitochondrial fusion in a mitofusin-dependent manner, suppresses spurious ciliation and maintains centrosome cohesion with ARL2 and Rootletin, supports centrosomal microtubule nucleation with ARL2/TBCD, regulates ATGL recruitment to lipid droplets via palmitoylation-dependent LD localization and Arf1-COPI modulation, participates in ARF6-dependent cytokinesis, and is required for TLR3-dependent antiviral interferon responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELMOD2 is a broadly-specific ARF-family GTPase-activating protein (GAP) that coordinates membrane and cytoskeletal dynamics across multiple organelles by acting both as a GAP and as a GTPase effector [#0]. It was first purified as a GAP for ARL2 that, unusually, also accelerates GTP hydrolysis on ARF proteins despite lacking the canonical ARF-GAP signature, defining an exceptionally broad ARF-family specificity [#0]. Working downstream of ARL2, ELMOD2 promotes mitofusin-dependent mitochondrial fusion, with ELMOD2, ARL2, MFN1/2, MIRO1/2 and mitoPLD co-localizing at discrete mitochondrial puncta; this fusion-promoting function is retained by a GAP-dead mutant, showing it is GAP-independent [#5], and ELMOD2-ARL2 interaction supports the mitochondrial dynamics required for meiotic progression [#4]. With ARL2 and Rootletin it suppresses spurious ciliation, maintains centrosome cohesion and regulates ciliary vesicle docking, functioning downstream of TTBK2 and upstream of CP110 [#7], and with ARL2/TBCD it supports centrosomal microtubule nucleation while separately acting with ARF6 in cytokinesis [#6]. At lipid droplets, ELMOD2 is anchored by palmitoylation and limits ATGL recruitment, with both its GAP activity and palmitoylation-dependent localization required to control cellular triglyceride levels [#2, #3]. ELMOD2 is also required for TLR3-dependent type I and III interferon expression in antiviral responses [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing the core biochemical activity: ELMOD2 was identified as a GAP for ARL2 that also acts on ARF proteins, defining it as a broad-specificity ARF-family GAP and the molecular basis for its later roles.\",\n      \"evidence\": \"Protein purification from bovine testis and in vitro GAP assays against ARL2 and ARF substrates\",\n      \"pmids\": [\"17452337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural basis for the broad specificity despite lacking the canonical ARF-GAP signature\",\n        \"Cellular substrates and physiological contexts not addressed\",\n        \"No partners beyond the tested GTPases identified\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First cellular role linked ELMOD2 to innate immunity, showing it is required for TLR3-driven antiviral interferon expression.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in A549 cells and macrophages with microarray, qPCR, and TLR3 activation readouts\",\n      \"pmids\": [\"19966137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular step in the TLR3 pathway connecting GAP activity to IFN induction not defined\",\n        \"Whether GAP activity or a specific GTPase partner is required not tested\",\n        \"Single lab, single cell-type panel\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a lipid-droplet function and the determinants required for it, showing ELMOD2 controls ATGL recruitment and triglyceride levels via palmitoylation-dependent LD localization and GAP activity.\",\n      \"evidence\": \"siRNA knockdown, GAP-dead and palmitoylation-deficient mutagenesis with siRNA-resistant rescue, triglyceride quantification, immunofluorescence, fractionation\",\n      \"pmids\": [\"25904333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The relevant GTPase substrate at lipid droplets not identified in this work\",\n        \"Palmitoylation enzyme(s) acting on ELMOD2 unknown\",\n        \"Mechanism connecting ELMOD2 to Arf1-COPI not directly demonstrated here\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Tied ELMOD2 physically and functionally to ARL2 in mitochondrial dynamics, showing the interaction is required for meiotic progression.\",\n      \"evidence\": \"Co-immunoprecipitation, co-localization, siRNA knockdown in mouse oocytes with ATP, polar body, and chromosome readouts\",\n      \"pmids\": [\"28324667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal or endogenous validation\",\n        \"Direct molecular mechanism linking ARL2 interaction to mitochondrial morphology not resolved\",\n        \"Whether GAP activity is required for the oocyte phenotype untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the mechanism of ELMOD2 in mitochondrial fusion, showing it acts downstream of ARL2 to promote mitofusin-dependent fusion independently of its GAP activity.\",\n      \"evidence\": \"CRISPR knockout, overexpression, GAP-dead mutagenesis, photoactivatable-GFP fusion-rate assays, and co-localization with ARL2/MFN1/2/MIRO1/2/mitoPLD\",\n      \"pmids\": [\"30865555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The non-catalytic (effector) mechanism by which ELMOD2 promotes fusion not defined\",\n        \"Direct interactions with mitofusins or MIRO proteins not established\",\n        \"Relationship of the fusion role to the lipid-droplet/ER localization unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated functional versatility by separating two centrosome/cytokinesis roles tied to distinct GTPase partners (ARL2/TBCD for microtubule nucleation; ARF6 for cytokinesis).\",\n      \"evidence\": \"ELMOD2 deletion in MEFs with myc-tagged rescue, microtubule nucleation and cytokinesis assays\",\n      \"pmids\": [\"32614697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ELMOD2 acts as GAP or effector in each role not fully delineated\",\n        \"Direct physical interaction with ARF6 and TBCD not biochemically mapped here\",\n        \"Spatial regulation directing ELMOD2 to distinct partners unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ELMOD2 in a defined ciliation-control pathway, showing it acts with ARL2 and Rootletin to suppress spurious ciliation and maintain centrosome cohesion within a TTBK2-to-CP110 axis.\",\n      \"evidence\": \"ELMOD2 and Rootletin deletion in MEFs, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, ciliary marker immunofluorescence\",\n      \"pmids\": [\"33596093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction among ELMOD2, ARL2, and Rootletin not shown\",\n        \"How ELMOD2 GAP activity feeds into Rootletin/rootlet maintenance unresolved\",\n        \"Mechanistic link to ciliary vesicle docking not detailed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single broad-specificity GAP is partitioned among mitochondria, lipid droplets, centrosomes, and immune signaling—and when it acts catalytically versus as a non-catalytic effector—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No unifying model for spatial/partner selection across organelles\",\n        \"Catalytic versus effector contributions not systematically separated across functions\",\n        \"No structural data explaining broad ARF-family specificity\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARL2\", \"ARF6\", \"TBCD\", \"Rootletin\", \"MFN1\", \"MFN2\", \"ATGL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}