{"gene":"ARCN1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2016,"finding":"ARCN1 encodes the delta subunit of the COPI coatomer complex, which is responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. Loss-of-function heterozygous mutations in ARCN1 cause defective type I collagen transport and reduced collagen secretion, leading to ER stress. This was established in ARCN1 mutant patient-derived cell lines showing ER stress markers and reduced collagen secretion, providing the mechanistic basis for the skeletal phenotype (micrognathia, rhizomelic shortening, microcephalic dwarfism) of the associated craniofacial syndrome.","method":"Patient-derived mutant cell line analysis (ER stress assays, collagen secretion assays); loss-of-function mutation analysis in human genetics cohort","journal":"American Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype (ER stress, reduced collagen secretion) in patient-derived cell lines with loss-of-function mutations; single study with two orthogonal cellular readouts but no in vitro reconstitution or structural validation","pmids":["27476655"],"is_preprint":false},{"year":2015,"finding":"ARCN1 is required for efficient influenza A virus replication. miR-33a suppresses ARCN1 protein expression by targeting its 3' UTR, and knockdown of ARCN1 phenocopies miR-33a overexpression by impeding virus replication at the stage of virus internalization. Ectopic expression of ARCN1 partially rescues the inhibitory effect of miR-33a on virus replication, establishing ARCN1 as a pro-viral host factor whose suppression by miR-33a restricts influenza A infection.","method":"Luciferase reporter assay (ARCN1 3' UTR), immunoblotting, siRNA knockdown of ARCN1, ectopic ARCN1 overexpression rescue experiment, miRNA overexpression in cell lines (293T, HeLa)","journal":"The Journal of General Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, knockdown, rescue by overexpression) in a single lab; functional link between ARCN1 suppression and viral internalization defect established by convergent evidence","pmids":["26498766"],"is_preprint":false}],"current_model":"ARCN1 encodes the delta subunit (δ-COP) of the COPI coatomer complex and mediates retrograde protein transport between the Golgi and endoplasmic reticulum; loss of ARCN1 function causes ER stress and defective type I collagen secretion underlying a human craniofacial/skeletal syndrome, and ARCN1 is also required as a host factor for influenza A virus internalization, a function exploited by miR-33a-mediated suppression to restrict viral replication."},"narrative":{"mechanistic_narrative":"ARCN1 encodes the delta subunit of the COPI coatomer complex, which mediates intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus [PMID:27476655]. Loss-of-function heterozygous mutations in ARCN1 impair type I collagen transport and reduce collagen secretion, triggering ER stress and underlying a craniofacial/skeletal syndrome characterized by micrognathia, rhizomelic shortening, and microcephalic dwarfism [PMID:27476655]. Independently, ARCN1 acts as a pro-viral host factor required for efficient influenza A virus internalization; its expression is suppressed by miR-33a through targeting of the ARCN1 3' UTR, and this suppression restricts viral replication [PMID:26498766]. Beyond these two functions, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Whether ARCN1 contributes to influenza A virus infection was unknown; this work established it as a pro-viral host factor whose suppression by a host miRNA limits viral entry.","evidence":"Luciferase 3' UTR reporter assay, siRNA knockdown, and ectopic ARCN1 overexpression rescue in 293T and HeLa cells","pmids":["26498766"],"confidence":"Medium","gaps":["The molecular step in internalization that requires ARCN1 is not defined","Whether ARCN1's COPI function is mechanistically involved in viral entry was not tested","No direct interaction between ARCN1 and viral components was demonstrated"]},{"year":2016,"claim":"The cellular consequence of ARCN1 loss-of-function in human disease was unresolved; patient-derived cells linked heterozygous mutations to impaired collagen secretion and ER stress, providing the basis for the skeletal/craniofacial syndrome.","evidence":"ER stress assays and collagen secretion assays in ARCN1 mutant patient-derived cell lines; loss-of-function mutation analysis in a human genetics cohort","pmids":["27476655"],"confidence":"Medium","gaps":["No in vitro reconstitution or structural validation of the delta-COP role was performed","Whether all secretory cargo or specifically collagen is affected was not delineated","The molecular basis for the tissue-specific (skeletal/craniofacial) phenotype is unexplained"]},{"year":null,"claim":"How ARCN1's role in COPI-mediated ER-Golgi transport mechanistically connects to its requirement during influenza A internalization remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ARCN1 within the COPI coatomer in the available corpus","No defined direct binding partners or substrates beyond inferred collagen cargo","Unclear whether the viral and secretory functions share a common molecular mechanism"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]}],"complexes":["COPI coatomer complex"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48444","full_name":"Coatomer subunit delta","aliases":["Archain","Delta-coat protein","Delta-COP"],"length_aa":511,"mass_kda":57.2,"function":"Component of the coatomer, a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. The coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors (By similarity)","subcellular_location":"Cytoplasm; Golgi apparatus membrane; Cytoplasmic vesicle, COPI-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P48444/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ARCN1","classification":"Common Essential","n_dependent_lines":1198,"n_total_lines":1208,"dependency_fraction":0.9917218543046358},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPA","stoichiometry":10.0},{"gene":"COPB2","stoichiometry":10.0},{"gene":"COPE","stoichiometry":10.0},{"gene":"COPG1","stoichiometry":10.0},{"gene":"SPTLC1","stoichiometry":4.0},{"gene":"PPM1G","stoichiometry":0.2},{"gene":"SCYL1","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARCN1","total_profiled":1310},"omim":[{"mim_id":"617164","title":"SHORT STATURE-MICROGNATHIA SYNDROME; SSMG","url":"https://www.omim.org/entry/617164"},{"mim_id":"602434","title":"ANCIENT UBIQUITOUS PROTEIN 1; AUP1","url":"https://www.omim.org/entry/602434"},{"mim_id":"600820","title":"ARCHAIN 1; ARCN1","url":"https://www.omim.org/entry/600820"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARCN1"},"hgnc":{"alias_symbol":["delta-COP"],"prev_symbol":["COPD"]},"alphafold":{"accession":"P48444","domains":[{"cath_id":"3.30.450.60","chopping":"2-134","consensus_level":"high","plddt":89.2962,"start":2,"end":134},{"cath_id":"2.60.40.1170","chopping":"273-370_478-509","consensus_level":"medium","plddt":95.3614,"start":273,"end":509},{"cath_id":"2.60.40.1170","chopping":"376-473","consensus_level":"medium","plddt":95.2507,"start":376,"end":473}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48444","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48444-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48444-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARCN1","jax_strain_url":"https://www.jax.org/strain/search?query=ARCN1"},"sequence":{"accession":"P48444","fasta_url":"https://rest.uniprot.org/uniprotkb/P48444.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48444/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48444"}},"corpus_meta":[{"pmid":"19407051","id":"PMC_19407051","title":"Systemic manifestations and comorbidities of COPD.","date":"2009","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/19407051","citation_count":1194,"is_preprint":false},{"pmid":"17138679","id":"PMC_17138679","title":"Mortality in COPD: Role of comorbidities.","date":"2006","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/17138679","citation_count":766,"is_preprint":false},{"pmid":"32336666","id":"PMC_32336666","title":"Oxidative stress-based therapeutics in COPD.","date":"2020","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/32336666","citation_count":366,"is_preprint":false},{"pmid":"26363803","id":"PMC_26363803","title":"The relationship between COPD and lung cancer.","date":"2015","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/26363803","citation_count":329,"is_preprint":false},{"pmid":"10843965","id":"PMC_10843965","title":"Oxidants/antioxidants and COPD.","date":"2000","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/10843965","citation_count":283,"is_preprint":false},{"pmid":"31112385","id":"PMC_31112385","title":"Benralizumab for the Prevention of COPD Exacerbations.","date":"2019","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31112385","citation_count":271,"is_preprint":false},{"pmid":"16997739","id":"PMC_16997739","title":"Alveolar macrophages as orchestrators of COPD.","date":"2004","source":"COPD","url":"https://pubmed.ncbi.nlm.nih.gov/16997739","citation_count":244,"is_preprint":false},{"pmid":"18817512","id":"PMC_18817512","title":"Role of HDAC2 in the pathophysiology of COPD.","date":"2009","source":"Annual review of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18817512","citation_count":243,"is_preprint":false},{"pmid":"19020276","id":"PMC_19020276","title":"Obesity and the lung: 5. 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COPD.","date":"2017","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/28790817","citation_count":37,"is_preprint":false},{"pmid":"20965933","id":"PMC_20965933","title":"Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD.","date":"2010","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/20965933","citation_count":37,"is_preprint":false},{"pmid":"31190789","id":"PMC_31190789","title":"Targeting IL-5 in COPD.","date":"2019","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/31190789","citation_count":36,"is_preprint":false},{"pmid":"19017738","id":"PMC_19017738","title":"Translating the COPD transcriptome: insights into pathogenesis and tools for clinical management.","date":"2008","source":"Proceedings of the American Thoracic 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of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/26527870","citation_count":29,"is_preprint":false},{"pmid":"30190272","id":"PMC_30190272","title":"The DNA repair transcriptome in severe COPD.","date":"2018","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/30190272","citation_count":29,"is_preprint":false},{"pmid":"24147597","id":"PMC_24147597","title":"Sputum ADAM8 expression is increased in severe asthma and COPD.","date":"2014","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24147597","citation_count":29,"is_preprint":false},{"pmid":"18268923","id":"PMC_18268923","title":"A review of etiologies of depression in COPD.","date":"2007","source":"International journal of chronic obstructive pulmonary disease","url":"https://pubmed.ncbi.nlm.nih.gov/18268923","citation_count":29,"is_preprint":false},{"pmid":"23288549","id":"PMC_23288549","title":"Metabolic derangements in COPD muscle dysfunction.","date":"2013","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/23288549","citation_count":28,"is_preprint":false},{"pmid":"26204554","id":"PMC_26204554","title":"Prostanoids in Asthma and COPD: Actions, Dysregulation, and Therapeutic Opportunities.","date":"2015","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/26204554","citation_count":27,"is_preprint":false},{"pmid":"32799375","id":"PMC_32799375","title":"RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD.","date":"2020","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/32799375","citation_count":27,"is_preprint":false},{"pmid":"37147634","id":"PMC_37147634","title":"Extracellular vesicles and COPD: foe or friend?","date":"2023","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37147634","citation_count":26,"is_preprint":false},{"pmid":"35382831","id":"PMC_35382831","title":"Extracellular vesicles and chronic obstructive pulmonary disease (COPD): a systematic review.","date":"2022","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/35382831","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43927,"output_tokens":1050,"usd":0.073765,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7218,"output_tokens":1288,"usd":0.034145,"stage2_stop_reason":"end_turn"},"total_usd":0.10791,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the 100 papers, I need to identify which ones are actually about ARCN1 (delta-COP, the coatomer subunit delta of COPI). \n\nThe vast majority of papers (1-13, 15-87, 89-100) are about COPD (chronic obstructive pulmonary disease) — a completely different entity. These are a symbol collision: \"COPD\" is an alias for ARCN1 in HGNC, but these papers are about the lung disease, not the protein.\n\nPaper [44] (PMID 27476655) is explicitly about ARCN1 mutations causing a craniofacial syndrome via COPI-mediated transport defects — this is clearly about the canonical protein.\n\nPaper [88] (PMID 26498766) is about miR-33a targeting ARCN1 to inhibit influenza A virus replication — this is about the canonical ARCN1 protein.\n\nThese are the only two papers describing mechanistic findings about ARCN1 the protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"ARCN1 encodes the delta subunit of the COPI coatomer complex, which is responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. Loss-of-function heterozygous mutations in ARCN1 cause defective type I collagen transport and reduced collagen secretion, leading to ER stress. This was established in ARCN1 mutant patient-derived cell lines showing ER stress markers and reduced collagen secretion, providing the mechanistic basis for the skeletal phenotype (micrognathia, rhizomelic shortening, microcephalic dwarfism) of the associated craniofacial syndrome.\",\n      \"method\": \"Patient-derived mutant cell line analysis (ER stress assays, collagen secretion assays); loss-of-function mutation analysis in human genetics cohort\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype (ER stress, reduced collagen secretion) in patient-derived cell lines with loss-of-function mutations; single study with two orthogonal cellular readouts but no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"27476655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ARCN1 is required for efficient influenza A virus replication. miR-33a suppresses ARCN1 protein expression by targeting its 3' UTR, and knockdown of ARCN1 phenocopies miR-33a overexpression by impeding virus replication at the stage of virus internalization. Ectopic expression of ARCN1 partially rescues the inhibitory effect of miR-33a on virus replication, establishing ARCN1 as a pro-viral host factor whose suppression by miR-33a restricts influenza A infection.\",\n      \"method\": \"Luciferase reporter assay (ARCN1 3' UTR), immunoblotting, siRNA knockdown of ARCN1, ectopic ARCN1 overexpression rescue experiment, miRNA overexpression in cell lines (293T, HeLa)\",\n      \"journal\": \"The Journal of General Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, knockdown, rescue by overexpression) in a single lab; functional link between ARCN1 suppression and viral internalization defect established by convergent evidence\",\n      \"pmids\": [\"26498766\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARCN1 encodes the delta subunit (δ-COP) of the COPI coatomer complex and mediates retrograde protein transport between the Golgi and endoplasmic reticulum; loss of ARCN1 function causes ER stress and defective type I collagen secretion underlying a human craniofacial/skeletal syndrome, and ARCN1 is also required as a host factor for influenza A virus internalization, a function exploited by miR-33a-mediated suppression to restrict viral replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARCN1 encodes the delta subunit of the COPI coatomer complex, which mediates intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus [#0]. Loss-of-function heterozygous mutations in ARCN1 impair type I collagen transport and reduce collagen secretion, triggering ER stress and underlying a craniofacial/skeletal syndrome characterized by micrognathia, rhizomelic shortening, and microcephalic dwarfism [#0]. Independently, ARCN1 acts as a pro-viral host factor required for efficient influenza A virus internalization; its expression is suppressed by miR-33a through targeting of the ARCN1 3' UTR, and this suppression restricts viral replication [#1]. Beyond these two functions, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether ARCN1 contributes to influenza A virus infection was unknown; this work established it as a pro-viral host factor whose suppression by a host miRNA limits viral entry.\",\n      \"evidence\": \"Luciferase 3' UTR reporter assay, siRNA knockdown, and ectopic ARCN1 overexpression rescue in 293T and HeLa cells\",\n      \"pmids\": [\"26498766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular step in internalization that requires ARCN1 is not defined\",\n        \"Whether ARCN1's COPI function is mechanistically involved in viral entry was not tested\",\n        \"No direct interaction between ARCN1 and viral components was demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The cellular consequence of ARCN1 loss-of-function in human disease was unresolved; patient-derived cells linked heterozygous mutations to impaired collagen secretion and ER stress, providing the basis for the skeletal/craniofacial syndrome.\",\n      \"evidence\": \"ER stress assays and collagen secretion assays in ARCN1 mutant patient-derived cell lines; loss-of-function mutation analysis in a human genetics cohort\",\n      \"pmids\": [\"27476655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution or structural validation of the delta-COP role was performed\",\n        \"Whether all secretory cargo or specifically collagen is affected was not delineated\",\n        \"The molecular basis for the tissue-specific (skeletal/craniofacial) phenotype is unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARCN1's role in COPI-mediated ER-Golgi transport mechanistically connects to its requirement during influenza A internalization remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of ARCN1 within the COPI coatomer in the available corpus\",\n        \"No defined direct binding partners or substrates beyond inferred collagen cargo\",\n        \"Unclear whether the viral and secretory functions share a common molecular mechanism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"COPI coatomer complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}