{"gene":"STX16","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2005,"finding":"A cis-acting imprinting control element within STX16 is necessary for establishing and/or maintaining methylation at GNAS exon A/B; heterozygous microdeletions within STX16 (3-kb and 4.4-kb) that overlap by 1,286 bp cause loss of methylation at GNAS exon A/B when maternally transmitted, demonstrating that the overlapping region harbors the functional element. STX16 mRNA itself is expressed biallelically (not imprinted), ruling out STX16 haploinsufficiency as the mechanism.","method":"Identification of overlapping deletion boundaries by genetic mapping; STX16 expression analysis in lymphoblastoid cells of deletion carriers vs. controls to establish biallelic expression","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent deletion alleles with overlapping boundaries precisely define the functional element; biallelic expression confirmed by mRNA analysis; replicated across multiple kindreds in the same study","pmids":["15800843"],"is_preprint":false},{"year":2026,"finding":"STX16 is required for autophagolysosome biogenesis in hepatocellular carcinoma cells; STX16 deficiency (via gene editing) causes autophagosome accumulation, which are then packaged into extracellular vesicles and delivered to macrophages, triggering autophagic cell death and p62-guided STAT3 destruction in macrophages, thereby eliminating M2 tumor-associated macrophages. Upstream, lactylation of H3K9/H3K18 on the STX16 promoter drives STX16 transcription, linking metabolic (lactate) signaling to STX16 expression.","method":"STX16 gene editing, in vitro Transwell co-cultures, LC3-based autophagy tracing, RNA-seq, orthotopic xenograft models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STX16 gene editing with defined cellular phenotype (autophagosome accumulation, macrophage death) plus multiple orthogonal methods (LC3 tracing, RNA-seq, in vivo), single lab","pmids":["41731604"],"is_preprint":false}],"current_model":"STX16 encodes a syntaxin family protein whose genomic locus harbors a cis-acting imprinting control element required for methylation at the GNAS exon A/B differentially methylated region (maternally transmitted deletions disrupt this element causing AD-PHP1B); at the cellular level STX16 is required for autophagolysosome biogenesis, and its loss leads to autophagosome accumulation and extracellular vesicle-mediated transfer of autophagic cargo to macrophages, while its own transcription is regulated by H3K9/H3K18 lactylation downstream of cellular lactate metabolism."},"narrative":{"mechanistic_narrative":"STX16 occupies two distinct biological roles defined in the available corpus: a genomic-locus role in genomic imprinting and a protein-level role in autophagy. The STX16 locus harbors a cis-acting imprinting control element required for establishing or maintaining methylation at the GNAS exon A/B differentially methylated region; maternally transmitted heterozygous microdeletions within STX16 cause loss of methylation at GNAS exon A/B, and because STX16 mRNA is expressed biallelically, this imprinting defect reflects disruption of the cis-element rather than STX16 haploinsufficiency [PMID:15800843]. This locus is causally linked to autosomal dominant pseudohypoparathyroidism type 1B [PMID:15800843]. At the cellular level, STX16 is required for autophagolysosome biogenesis: its loss in hepatocellular carcinoma cells causes autophagosome accumulation, which are packaged into extracellular vesicles and delivered to macrophages where they trigger autophagic cell death and p62-guided STAT3 destruction, eliminating M2 tumor-associated macrophages; STX16 transcription is itself driven by H3K9/H3K18 lactylation at its promoter, coupling lactate metabolism to STX16 expression [PMID:41731604]. Beyond these two findings, no further mechanistic detail on STX16 protein function has been characterized in the available corpus.","teleology":[{"year":2005,"claim":"Established that the disease-causing element at the STX16 locus is a cis-acting imprinting control element, not the STX16 protein itself, resolving how STX16 deletions cause an imprinting disorder.","evidence":"Genetic mapping of overlapping microdeletion boundaries plus biallelic mRNA expression analysis in lymphoblastoid cells of deletion carriers","pmids":["15800843"],"confidence":"High","gaps":["The molecular identity and trans-acting factors binding the control element are not defined","Mechanism by which the element directs methylation at the distal GNAS exon A/B DMR is unresolved","No role for the STX16 protein in the imprinting phenotype is established"]},{"year":2026,"claim":"Defined a cellular function for the STX16 protein in autophagolysosome biogenesis and connected its expression to lactate-driven histone lactylation, framing STX16 as a metabolically regulated node in tumor-macrophage crosstalk.","evidence":"STX16 gene editing, LC3-based autophagy tracing, Transwell co-cultures, RNA-seq, and orthotopic xenograft models in hepatocellular carcinoma","pmids":["41731604"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Molecular mechanism by which STX16 promotes autophagosome-lysosome fusion is not resolved","Direct membrane/SNARE partners of STX16 in this process are not identified"]},{"year":null,"claim":"Whether the imprinting-locus role and the autophagy protein role are mechanistically related, and what STX16's direct molecular partners are, remains unknown.","evidence":"No discovery in the corpus connects the two functional contexts or identifies direct SNARE/membrane interactors","pmids":[],"confidence":"Low","gaps":["No direct physical partners of STX16 identified in the corpus","Subcellular localization of STX16 not directly established in the timeline","No structural model linking sequence to function"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14662","full_name":"Syntaxin-16","aliases":[],"length_aa":325,"mass_kda":37.0,"function":"SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O14662/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STX16","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000124222","cell_line_id":"CID000764","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"STX10","stoichiometry":10.0},{"gene":"STX16;STX16-NPEPL1","stoichiometry":10.0},{"gene":"BNIP1","stoichiometry":4.0},{"gene":"SCFD1","stoichiometry":4.0},{"gene":"NSF","stoichiometry":4.0},{"gene":"STX6","stoichiometry":4.0},{"gene":"NAPA","stoichiometry":0.2},{"gene":"STX18","stoichiometry":0.2},{"gene":"VPS45","stoichiometry":0.2},{"gene":"ZW10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000764","total_profiled":1310},"omim":[{"mim_id":"615285","title":"NEUTROPENIA, SEVERE CONGENITAL, 5, AUTOSOMAL RECESSIVE; SCN5","url":"https://www.omim.org/entry/615285"},{"mim_id":"610089","title":"RAD50-INTERACTING PROTEIN 1; RINT1","url":"https://www.omim.org/entry/610089"},{"mim_id":"610035","title":"VACUOLAR PROTEIN SORTING 45 HOMOLOG; VPS45","url":"https://www.omim.org/entry/610035"},{"mim_id":"603666","title":"SYNTAXIN 16; STX16","url":"https://www.omim.org/entry/603666"},{"mim_id":"603233","title":"PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B","url":"https://www.omim.org/entry/603233"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STX16"},"hgnc":{"alias_symbol":["hsyn16","SYN16","SYN-16"],"prev_symbol":[]},"alphafold":{"accession":"O14662","domains":[{"cath_id":"1.20.58.70","chopping":"78-200_223-265","consensus_level":"high","plddt":84.5578,"start":78,"end":265},{"cath_id":"1.20.5","chopping":"267-314","consensus_level":"medium","plddt":83.8846,"start":267,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14662","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14662-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14662-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX16","jax_strain_url":"https://www.jax.org/strain/search?query=STX16"},"sequence":{"accession":"O14662","fasta_url":"https://rest.uniprot.org/uniprotkb/O14662.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14662/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14662"}},"corpus_meta":[{"pmid":"15800843","id":"PMC_15800843","title":"A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15800843","citation_count":159,"is_preprint":false},{"pmid":"24438374","id":"PMC_24438374","title":"Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24438374","citation_count":54,"is_preprint":false},{"pmid":"23087324","id":"PMC_23087324","title":"De novo STX16 deletions: an infrequent cause of pseudohypoparathyroidism type Ib that should be excluded in sporadic cases.","date":"2012","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23087324","citation_count":29,"is_preprint":false},{"pmid":"27338644","id":"PMC_27338644","title":"Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27338644","citation_count":20,"is_preprint":false},{"pmid":"32337648","id":"PMC_32337648","title":"A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B.","date":"2020","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/32337648","citation_count":18,"is_preprint":false},{"pmid":"34477200","id":"PMC_34477200","title":"Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions.","date":"2022","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34477200","citation_count":12,"is_preprint":false},{"pmid":"33247854","id":"PMC_33247854","title":"Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion.","date":"2020","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/33247854","citation_count":8,"is_preprint":false},{"pmid":"35119251","id":"PMC_35119251","title":"Autosomal dominant pseudohypoparathyroidism type 1b due to STX16 deletion: a case presentation and literature review.","date":"2022","source":"Minerva endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35119251","citation_count":1,"is_preprint":false},{"pmid":"38095637","id":"PMC_38095637","title":"Intrafamilial phenotypic heterogeneity in siblings with pseudohypoparathyroidism 1B due to maternal STX16 deletion.","date":"2023","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/38095637","citation_count":0,"is_preprint":false},{"pmid":"41731604","id":"PMC_41731604","title":"Icaritin eliminates tumor-associated macrophages via STX16-dependent extracellular vesicle delivery of autophagosomes from hepatocellular carcinoma cells.","date":"2026","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41731604","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.09.648028","title":"Rapid expansion of synaptic complexity as a key contributor to cognitive growth in early humans","date":"2025-04-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.09.648028","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8343,"output_tokens":795,"usd":0.018477,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7205,"output_tokens":1395,"usd":0.03545,"stage2_stop_reason":"end_turn"},"total_usd":0.053927,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"A cis-acting imprinting control element within STX16 is necessary for establishing and/or maintaining methylation at GNAS exon A/B; heterozygous microdeletions within STX16 (3-kb and 4.4-kb) that overlap by 1,286 bp cause loss of methylation at GNAS exon A/B when maternally transmitted, demonstrating that the overlapping region harbors the functional element. STX16 mRNA itself is expressed biallelically (not imprinted), ruling out STX16 haploinsufficiency as the mechanism.\",\n      \"method\": \"Identification of overlapping deletion boundaries by genetic mapping; STX16 expression analysis in lymphoblastoid cells of deletion carriers vs. controls to establish biallelic expression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent deletion alleles with overlapping boundaries precisely define the functional element; biallelic expression confirmed by mRNA analysis; replicated across multiple kindreds in the same study\",\n      \"pmids\": [\"15800843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STX16 is required for autophagolysosome biogenesis in hepatocellular carcinoma cells; STX16 deficiency (via gene editing) causes autophagosome accumulation, which are then packaged into extracellular vesicles and delivered to macrophages, triggering autophagic cell death and p62-guided STAT3 destruction in macrophages, thereby eliminating M2 tumor-associated macrophages. Upstream, lactylation of H3K9/H3K18 on the STX16 promoter drives STX16 transcription, linking metabolic (lactate) signaling to STX16 expression.\",\n      \"method\": \"STX16 gene editing, in vitro Transwell co-cultures, LC3-based autophagy tracing, RNA-seq, orthotopic xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STX16 gene editing with defined cellular phenotype (autophagosome accumulation, macrophage death) plus multiple orthogonal methods (LC3 tracing, RNA-seq, in vivo), single lab\",\n      \"pmids\": [\"41731604\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX16 encodes a syntaxin family protein whose genomic locus harbors a cis-acting imprinting control element required for methylation at the GNAS exon A/B differentially methylated region (maternally transmitted deletions disrupt this element causing AD-PHP1B); at the cellular level STX16 is required for autophagolysosome biogenesis, and its loss leads to autophagosome accumulation and extracellular vesicle-mediated transfer of autophagic cargo to macrophages, while its own transcription is regulated by H3K9/H3K18 lactylation downstream of cellular lactate metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STX16 occupies two distinct biological roles defined in the available corpus: a genomic-locus role in genomic imprinting and a protein-level role in autophagy. The STX16 locus harbors a cis-acting imprinting control element required for establishing or maintaining methylation at the GNAS exon A/B differentially methylated region; maternally transmitted heterozygous microdeletions within STX16 cause loss of methylation at GNAS exon A/B, and because STX16 mRNA is expressed biallelically, this imprinting defect reflects disruption of the cis-element rather than STX16 haploinsufficiency [#0]. This locus is causally linked to autosomal dominant pseudohypoparathyroidism type 1B [#0]. At the cellular level, STX16 is required for autophagolysosome biogenesis: its loss in hepatocellular carcinoma cells causes autophagosome accumulation, which are packaged into extracellular vesicles and delivered to macrophages where they trigger autophagic cell death and p62-guided STAT3 destruction, eliminating M2 tumor-associated macrophages; STX16 transcription is itself driven by H3K9/H3K18 lactylation at its promoter, coupling lactate metabolism to STX16 expression [#1]. Beyond these two findings, no further mechanistic detail on STX16 protein function has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that the disease-causing element at the STX16 locus is a cis-acting imprinting control element, not the STX16 protein itself, resolving how STX16 deletions cause an imprinting disorder.\",\n      \"evidence\": \"Genetic mapping of overlapping microdeletion boundaries plus biallelic mRNA expression analysis in lymphoblastoid cells of deletion carriers\",\n      \"pmids\": [\n        \"15800843\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular identity and trans-acting factors binding the control element are not defined\",\n        \"Mechanism by which the element directs methylation at the distal GNAS exon A/B DMR is unresolved\",\n        \"No role for the STX16 protein in the imprinting phenotype is established\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a cellular function for the STX16 protein in autophagolysosome biogenesis and connected its expression to lactate-driven histone lactylation, framing STX16 as a metabolically regulated node in tumor-macrophage crosstalk.\",\n      \"evidence\": \"STX16 gene editing, LC3-based autophagy tracing, Transwell co-cultures, RNA-seq, and orthotopic xenograft models in hepatocellular carcinoma\",\n      \"pmids\": [\n        \"41731604\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Molecular mechanism by which STX16 promotes autophagosome-lysosome fusion is not resolved\",\n        \"Direct membrane/SNARE partners of STX16 in this process are not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the imprinting-locus role and the autophagy protein role are mechanistically related, and what STX16's direct molecular partners are, remains unknown.\",\n      \"evidence\": \"No discovery in the corpus connects the two functional contexts or identifies direct SNARE/membrane interactors\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct physical partners of STX16 identified in the corpus\",\n        \"Subcellular localization of STX16 not directly established in the timeline\",\n        \"No structural model linking sequence to function\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}