{"gene":"SEC16B","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2011,"finding":"Sec16B localizes to ER exit sites and acts as a scaffold for COPII coat assembly, defining transitional ER (tER) sites in mammalian cells. Knockdown of Sec16B (but not Sec16A) inhibited transport of the peroxisomal membrane biogenesis factor Pex16 from the ER to peroxisomes and suppressed Pex3 expression, while overexpressed Sec16B redistributed Pex3 and Pex16 from peroxisomes to ER membranes; RNAi-resistant Sec16B rescued these phenotypes.","method":"RNAi knockdown, overexpression, immunofluorescence microscopy, Western blot, rescue experiment with RNAi-resistant construct","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with defined phenotypic readout and rescue, replicated across two orthogonal perturbations","pmids":["21768384"],"is_preprint":false},{"year":2011,"finding":"The C-terminal region of Sec16B, which is not conserved in Sec16A, is required for its role in peroxisomal biogenesis factor transport from the ER, distinguishing Sec16B function from Sec16A at ER regions outside canonical ER exit sites.","method":"Domain deletion analysis, overexpression of truncation mutants, fluorescence microscopy","journal":"Cellular logistics","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis with functional readout, single lab single study","pmids":["22279616"],"is_preprint":false},{"year":2011,"finding":"Human Sec16B and Sec16A show distinct localization and dynamics at transitional ER; Sec16B is not functionally redundant with Sec16A, indicating specialized non-overlapping roles for the two isoforms.","method":"Live-cell imaging, FRAP, siRNA knockdown, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and dynamics experiments with functional comparison, single lab","pmids":["22355596"],"is_preprint":false},{"year":2020,"finding":"Sec16B is an ER stress-inducible gene: its mRNA is upregulated by thapsigargin and brefeldin A in Neuro2a cells. A functional unfolded protein response element (UPRE) in the Sec16B promoter responds to ER stress and spliced XBP1 overexpression, and a unique ATF4-responsive sequence in the first intron was also identified.","method":"Microarray, RT-PCR, luciferase reporter assay, sXBP1 overexpression","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays with defined regulatory elements, single lab","pmids":["32815086"],"is_preprint":false},{"year":2023,"finding":"A homozygous missense mutation in SEC16B in a patient with osteogenesis imperfecta caused type I procollagen accumulation in the ER and a general ER trafficking defect in patient fibroblasts. Transfection of wild-type SEC16B into patient cells rescued collagen trafficking, demonstrating that SEC16B is required for procollagen ER export.","method":"Patient fibroblast analysis, immunofluorescence, ER trafficking assay, rescue by wild-type transfection, proteomics","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 — human disease mutation with rescue experiment and multiple orthogonal methods (trafficking assay, ER stress markers, autophagosome quantification)","pmids":["36916446"],"is_preprint":false},{"year":2023,"finding":"Intestinal-specific knockout of Sec16b in mice impairs apoB lipidation and chylomicron secretion, reducing postprandial serum triglyceride output after intragastric lipid load or HFD refeeding, and protects female mice from HFD-induced obesity.","method":"Conditional (intestinal) knockout mouse model, acute oil challenge, fasting/HFD refeeding, serum triglyceride measurement, biochemical and imaging analyses","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean tissue-specific KO with defined mechanistic phenotype (apoB lipidation, chylomicron secretion), multiple assays","pmids":["36796587"],"is_preprint":false},{"year":2025,"finding":"Sec16b deletion in mice causes glucose intolerance under standard diet and high-fat diet conditions. Mechanistically, Sec16b deficiency impairs glucose-stimulated insulin secretion in pancreatic beta cells by downregulating cholinergic signaling and compromising intracellular Ca2+ influx.","method":"Conditional knockout mouse model, glucose/insulin tolerance tests, immunostaining, glucose-stimulated insulin secretion assay, RNA-seq of pancreatic islets, Drosophila RNAi epistasis","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1–2 — KO mouse model with mechanistic dissection via GSIS assay, Ca2+ measurements, RNA-seq, and conserved across Drosophila model","pmids":["40705078"],"is_preprint":false},{"year":2026,"finding":"SEC16B functions as a lipid-responsive regulator in the liver. Hepatic Sec16b deficiency decreases VLDL secretion through mechanisms partially independent of MTP-mediated ApoB lipidation and COPII-mediated trafficking. SEC16B partially localizes at ER–lipid droplet (LD) contact sites and promotes LD expansion by facilitating targeting of ER proteins to LDs. Hepatic Sec16b suppression lowers serum lipids and reduces atherosclerotic lesion size in Ldlr-null mice.","method":"Hepatic conditional knockout, VLDL secretion assay, ER–LD contact site imaging, MTP inhibitor comparison, atherosclerosis mouse model (Ldlr-null)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — liver-specific KO with multiple mechanistic readouts (VLDL secretion, LD contact sites, in vivo atherosclerosis), multiple orthogonal methods","pmids":["42030462"],"is_preprint":false},{"year":2026,"finding":"SEC16B acts as a tissue-selective modulator of COPII machinery in the liver, acting as a molecular brake to fine-tune COPII condensation for lipoprotein (APOB-containing) export. Hepatic deletion of SEC16B markedly reduces circulating APOB, triglycerides, and cholesterol, and protects against atherosclerosis and cardiac dysfunction. SEC16B expression is regulated by HNF4A.","method":"Hepatic knockout mouse model, integrative bioinformatics, AI-driven COPII condensation prediction, UK Biobank mining, atherosclerosis and cardiac function assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined molecular mechanism (COPII modulation), multiple in vivo phenotypic readouts, transcription factor regulation identified","pmids":["42032080"],"is_preprint":false}],"current_model":"SEC16B is a scaffold protein at ER exit sites that modulates COPII vesicle assembly for export of diverse cargoes including procollagen, APOB-containing lipoproteins (VLDL and chylomicrons), and peroxisomal biogenesis factors (Pex16/Pex3); it also localizes at ER–lipid droplet contact sites to promote lipid droplet expansion, is transcriptionally induced by ER stress via XBP1/ATF4, and in pancreatic beta cells supports cholinergic-driven Ca2+ influx and glucose-stimulated insulin secretion."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that SEC16B is a non-redundant COPII scaffold at ER exit sites resolved the question of whether the two mammalian Sec16 paralogs serve overlapping or distinct functions, and revealed a specific role for SEC16B in ER-to-peroxisome trafficking of Pex16 and Pex3.","evidence":"RNAi knockdown, overexpression, rescue with RNAi-resistant construct, FRAP, and domain-deletion analysis in mammalian cells","pmids":["21768384","22279616","22355596"],"confidence":"High","gaps":["Mechanism by which the SEC16B C-terminal domain specifically recognizes peroxisomal cargo is unknown","Whether SEC16B interacts directly with Pex16/Pex3 or acts indirectly through COPII components was not determined"]},{"year":2020,"claim":"Identifying ER stress-responsive regulatory elements (UPRE and ATF4-binding site) in the SEC16B locus established that SEC16B expression is transcriptionally upregulated during the unfolded protein response, linking ER proteostasis to COPII capacity.","evidence":"Microarray, RT-PCR, and luciferase reporter assays with XBP1 and ATF4 in Neuro2a cells","pmids":["32815086"],"confidence":"Medium","gaps":["Functional consequence of ER stress-induced SEC16B upregulation on COPII trafficking throughput was not measured","Whether the UPRE and ATF4 elements are conserved across species or cell types was not examined"]},{"year":2023,"claim":"Discovery that a homozygous SEC16B missense mutation causes osteogenesis imperfecta, with procollagen accumulation in the ER rescued by wild-type SEC16B, proved that SEC16B is essential for large-cargo ER export in humans and linked it to a Mendelian disease.","evidence":"Patient fibroblast analysis with immunofluorescence, ER trafficking assays, and wild-type rescue transfection","pmids":["36916446"],"confidence":"High","gaps":["How SEC16B enables packaging of oversized procollagen into COPII carriers is mechanistically unresolved","Whether other collagen types or large ECM cargoes are similarly affected was not tested"]},{"year":2023,"claim":"Intestinal-specific Sec16b knockout demonstrated that SEC16B is required for apoB lipidation and chylomicron secretion, establishing it as a rate-limiting factor in dietary lipid absorption and a contributor to diet-induced obesity.","evidence":"Conditional intestinal knockout mice with acute lipid challenge, fasting/HFD refeeding, and serum triglyceride measurements","pmids":["36796587"],"confidence":"High","gaps":["Whether SEC16B directly participates in pre-chylomicron transport vesicle formation or acts upstream on apoB lipidation was not resolved","Sex-specific protection from obesity (female mice) was not mechanistically explained"]},{"year":2025,"claim":"Sec16b deletion in pancreatic beta cells revealed an unexpected role in glucose-stimulated insulin secretion via cholinergic signaling and Ca²⁺ influx, extending SEC16B function beyond ER export scaffolding to endocrine cell physiology.","evidence":"Conditional knockout mice, GSIS assays, intracellular Ca²⁺ measurements, islet RNA-seq, and Drosophila RNAi epistasis","pmids":["40705078"],"confidence":"High","gaps":["The molecular link between SEC16B and cholinergic receptor surface expression or signaling is undefined","Whether the insulin secretion defect reflects impaired COPII-mediated trafficking of specific ion channels or receptors was not determined"]},{"year":2026,"claim":"Hepatic Sec16b studies revealed a dual mechanism: SEC16B acts as a molecular brake fine-tuning COPII condensation for APOB-lipoprotein export and also localizes to ER–lipid droplet contact sites to promote LD expansion, with hepatic deletion reducing serum lipids and atherosclerosis.","evidence":"Hepatic conditional knockout mice, VLDL secretion assays, ER–LD contact site imaging, atherosclerosis models (Ldlr-null), HNF4A transcriptional regulation, and AI-driven COPII condensation modeling","pmids":["42030462","42032080"],"confidence":"High","gaps":["Structural basis for SEC16B's brake function on COPII condensation lacks experimental validation","How SEC16B is targeted to ER–LD contact sites and whether it interacts with known LD-tethering machinery is unknown","Long-term metabolic consequences of hepatic SEC16B loss remain to be assessed"]},{"year":null,"claim":"The structural basis of SEC16B's distinct C-terminal domain, its mechanism for modulating COPII condensate dynamics, and the molecular pathway linking it to cholinergic signaling in beta cells remain open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of SEC16B or its COPII interaction interfaces exists","Whether SEC16B directly contacts APOB or acts solely through COPII remodeling is unresolved","Cell-type-specific roles beyond intestine, liver, and beta cells are largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,4,7]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4,5,7,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4]}],"complexes":["COPII coat"],"partners":["SEC16A","PEX16","PEX3","APOB","HNF4A","XBP1","ATF4"],"other_free_text":[]},"mechanistic_narrative":"SEC16B is a scaffold protein at ER exit sites that organizes COPII vesicle assembly for the export of diverse cargoes, including peroxisomal biogenesis factors (Pex16, Pex3), type I procollagen, and large APOB-containing lipoproteins (chylomicrons and VLDL), with its C-terminal domain conferring functions distinct from the paralog SEC16A [PMID:21768384, PMID:22279616, PMID:36916446, PMID:36796587]. In the liver, SEC16B fine-tunes COPII condensation to calibrate lipoprotein export, is transcriptionally regulated by HNF4A, and additionally localizes to ER–lipid droplet contact sites where it promotes lipid droplet expansion; hepatic deletion markedly lowers circulating APOB, triglycerides, and cholesterol and protects against atherosclerosis [PMID:42030462, PMID:42032080]. SEC16B is transcriptionally induced by ER stress through XBP1- and ATF4-responsive elements in its promoter and first intron [PMID:32815086], and in pancreatic beta cells it supports cholinergic signaling and Ca²⁺-dependent glucose-stimulated insulin secretion [PMID:40705078]. A homozygous loss-of-function SEC16B mutation causes osteogenesis imperfecta through impaired procollagen ER export [PMID:36916446]."},"prefetch_data":{"uniprot":{"accession":"Q96JE7","full_name":"Protein transport protein Sec16B","aliases":["Leucine zipper transcription regulator 2","Regucalcin gene promoter region-related protein p117","RGPR-p117","SEC16 homolog B"],"length_aa":1060,"mass_kda":116.6,"function":"Plays a role in the organization of the endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER). Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus (PubMed:17192411, PubMed:21768384, PubMed:22355596). Involved in peroxisome biogenesis. Regulates the transport of peroxisomal biogenesis factors PEX3 and PEX16 from the ER to peroxisomes (PubMed:21768384)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q96JE7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC16B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEC16B","total_profiled":1310},"omim":[{"mim_id":"612883","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 3; MENAQ3","url":"https://www.omim.org/entry/612883"},{"mim_id":"612882","title":"MENARCHE, AGE AT, QUANTITATIVE TRAIT LOCUS 2; MENAQ2","url":"https://www.omim.org/entry/612882"},{"mim_id":"612855","title":"SEC16 HOMOLOG B, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16B","url":"https://www.omim.org/entry/612855"},{"mim_id":"612854","title":"SEC16 HOMOLOG A, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16A","url":"https://www.omim.org/entry/612854"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":27.7},{"tissue":"liver","ntpm":38.6}],"url":"https://www.proteinatlas.org/search/SEC16B"},"hgnc":{"alias_symbol":["RGPR-p117","RGPR","Sec16S"],"prev_symbol":["LZTR2"]},"alphafold":{"accession":"Q96JE7","domains":[{"cath_id":"-","chopping":"281-294_304-327_625-688_699-711","consensus_level":"medium","plddt":87.4106,"start":281,"end":711}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JE7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JE7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JE7-F1-predicted_aligned_error_v6.png","plddt_mean":55.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC16B","jax_strain_url":"https://www.jax.org/strain/search?query=SEC16B"},"sequence":{"accession":"Q96JE7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JE7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JE7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JE7"}},"corpus_meta":[{"pmid":"19851340","id":"PMC_19851340","title":"Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population.","date":"2009","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19851340","citation_count":102,"is_preprint":false},{"pmid":"21768384","id":"PMC_21768384","title":"Sec16B is involved in the endoplasmic reticulum export of the peroxisomal membrane biogenesis factor peroxin 16 (Pex16) in mammalian cells.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21768384","citation_count":72,"is_preprint":false},{"pmid":"25637721","id":"PMC_25637721","title":"Genetic variations in SEC16B, MC4R, MAP2K5 and KCTD15 were associated with childhood obesity and interacted with dietary behaviors in Chinese school-age population.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25637721","citation_count":37,"is_preprint":false},{"pmid":"24670271","id":"PMC_24670271","title":"Association study of common polymorphisms in MSRA, TFAP2B, MC4R, NRXN3, PPARGC1A, TMEM18, SEC16B, HOXB5 and OLFM4 genes with obesity-related traits among Portuguese children.","date":"2014","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24670271","citation_count":34,"is_preprint":false},{"pmid":"19214710","id":"PMC_19214710","title":"Novel protein RGPR-p117: its role as the regucalcin gene transcription factor.","date":"2009","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19214710","citation_count":28,"is_preprint":false},{"pmid":"22355596","id":"PMC_22355596","title":"Characterization of human Sec16B: indications of specialized, non-redundant functions.","date":"2011","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/22355596","citation_count":25,"is_preprint":false},{"pmid":"30026463","id":"PMC_30026463","title":"Genetic variants in SEC16B are associated with body composition in black South Africans.","date":"2018","source":"Nutrition & diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30026463","citation_count":22,"is_preprint":false},{"pmid":"36796587","id":"PMC_36796587","title":"Intestinal SEC16B modulates obesity by regulating chylomicron metabolism.","date":"2023","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36796587","citation_count":16,"is_preprint":false},{"pmid":"16676356","id":"PMC_16676356","title":"Overexpression of RGPR-p117 enhances regucalcin gene promoter activity in cloned normal rat kidney proximal tubular epithelial cells: involvement of TTGGC motif.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16676356","citation_count":15,"is_preprint":false},{"pmid":"36916446","id":"PMC_36916446","title":"Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress.","date":"2023","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36916446","citation_count":14,"is_preprint":false},{"pmid":"16211248","id":"PMC_16211248","title":"Nuclear localization of a novel protein, RGPR-p117, in cloned normal rat kidney proximal tubular epithelial cells.","date":"2005","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16211248","citation_count":13,"is_preprint":false},{"pmid":"22279616","id":"PMC_22279616","title":"Dual function of Sec16B: Endoplasmic reticulum-derived protein secretion and peroxisome biogenesis in mammalian cells.","date":"2011","source":"Cellular logistics","url":"https://pubmed.ncbi.nlm.nih.gov/22279616","citation_count":9,"is_preprint":false},{"pmid":"32815086","id":"PMC_32815086","title":"Transcriptional regulation of the ER stress-inducible gene Sec16B in Neuro2a cells.","date":"2020","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32815086","citation_count":5,"is_preprint":false},{"pmid":"17549392","id":"PMC_17549392","title":"Overexpression of RGPR-p117 induces the decrease in protein and DNA contents in cloned normal rat kidney proximal tubular epithelial NRK52E cells.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17549392","citation_count":5,"is_preprint":false},{"pmid":"27655580","id":"PMC_27655580","title":"[Association between SEC16B polymorphisms and body mass index variation or risk of obesity: a Meta-analysis].","date":"2016","source":"Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/27655580","citation_count":3,"is_preprint":false},{"pmid":"35835253","id":"PMC_35835253","title":"The overexpressed transcription factor RGPR-p117 suppresses the proliferation of normal rat kidney proximal tubular epithelial NRK-52E cells: Involvement of diverse signaling pathways.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35835253","citation_count":3,"is_preprint":false},{"pmid":"39780531","id":"PMC_39780531","title":"Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells.","date":"2025","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/39780531","citation_count":3,"is_preprint":false},{"pmid":"33958541","id":"PMC_33958541","title":"Female-Specific Susceptibility Locus in BOC and SEC16B are Associated with Adolescent Idiopathic Scoliosis.","date":"2021","source":"Spine","url":"https://pubmed.ncbi.nlm.nih.gov/33958541","citation_count":2,"is_preprint":false},{"pmid":"40735296","id":"PMC_40735296","title":"Single-Cell RNA Sequencing Reveals the Critical Role of SEC16B in Lung Metastasis of Osteosarcoma.","date":"2025","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/40735296","citation_count":1,"is_preprint":false},{"pmid":"40705078","id":"PMC_40705078","title":"Identification of SEC16B as a novel regulator of glucose homeostasis.","date":"2025","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/40705078","citation_count":1,"is_preprint":false},{"pmid":"40907915","id":"PMC_40907915","title":"The advanced role of the transcription factor RGPR-p117 in cell regulation: Its involvement in transcription, cell growth, and lipid metabolism.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40907915","citation_count":1,"is_preprint":false},{"pmid":"42030462","id":"PMC_42030462","title":"Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion.","date":"2026","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/42030462","citation_count":0,"is_preprint":false},{"pmid":"42032080","id":"PMC_42032080","title":"Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export.","date":"2026","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/42032080","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.02.685776","title":"Adaptive introgression from Pacific herring to Atlantic herring in the brackish Baltic 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Knockdown of Sec16B (but not Sec16A) inhibited transport of the peroxisomal membrane biogenesis factor Pex16 from the ER to peroxisomes and suppressed Pex3 expression, while overexpressed Sec16B redistributed Pex3 and Pex16 from peroxisomes to ER membranes; RNAi-resistant Sec16B rescued these phenotypes.\",\n      \"method\": \"RNAi knockdown, overexpression, immunofluorescence microscopy, Western blot, rescue experiment with RNAi-resistant construct\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with defined phenotypic readout and rescue, replicated across two orthogonal perturbations\",\n      \"pmids\": [\"21768384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal region of Sec16B, which is not conserved in Sec16A, is required for its role in peroxisomal biogenesis factor transport from the ER, distinguishing Sec16B function from Sec16A at ER regions outside canonical ER exit sites.\",\n      \"method\": \"Domain deletion analysis, overexpression of truncation mutants, fluorescence microscopy\",\n      \"journal\": \"Cellular logistics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with functional readout, single lab single study\",\n      \"pmids\": [\"22279616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human Sec16B and Sec16A show distinct localization and dynamics at transitional ER; Sec16B is not functionally redundant with Sec16A, indicating specialized non-overlapping roles for the two isoforms.\",\n      \"method\": \"Live-cell imaging, FRAP, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and dynamics experiments with functional comparison, single lab\",\n      \"pmids\": [\"22355596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sec16B is an ER stress-inducible gene: its mRNA is upregulated by thapsigargin and brefeldin A in Neuro2a cells. A functional unfolded protein response element (UPRE) in the Sec16B promoter responds to ER stress and spliced XBP1 overexpression, and a unique ATF4-responsive sequence in the first intron was also identified.\",\n      \"method\": \"Microarray, RT-PCR, luciferase reporter assay, sXBP1 overexpression\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays with defined regulatory elements, single lab\",\n      \"pmids\": [\"32815086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous missense mutation in SEC16B in a patient with osteogenesis imperfecta caused type I procollagen accumulation in the ER and a general ER trafficking defect in patient fibroblasts. Transfection of wild-type SEC16B into patient cells rescued collagen trafficking, demonstrating that SEC16B is required for procollagen ER export.\",\n      \"method\": \"Patient fibroblast analysis, immunofluorescence, ER trafficking assay, rescue by wild-type transfection, proteomics\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — human disease mutation with rescue experiment and multiple orthogonal methods (trafficking assay, ER stress markers, autophagosome quantification)\",\n      \"pmids\": [\"36916446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal-specific knockout of Sec16b in mice impairs apoB lipidation and chylomicron secretion, reducing postprandial serum triglyceride output after intragastric lipid load or HFD refeeding, and protects female mice from HFD-induced obesity.\",\n      \"method\": \"Conditional (intestinal) knockout mouse model, acute oil challenge, fasting/HFD refeeding, serum triglyceride measurement, biochemical and imaging analyses\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with defined mechanistic phenotype (apoB lipidation, chylomicron secretion), multiple assays\",\n      \"pmids\": [\"36796587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec16b deletion in mice causes glucose intolerance under standard diet and high-fat diet conditions. Mechanistically, Sec16b deficiency impairs glucose-stimulated insulin secretion in pancreatic beta cells by downregulating cholinergic signaling and compromising intracellular Ca2+ influx.\",\n      \"method\": \"Conditional knockout mouse model, glucose/insulin tolerance tests, immunostaining, glucose-stimulated insulin secretion assay, RNA-seq of pancreatic islets, Drosophila RNAi epistasis\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO mouse model with mechanistic dissection via GSIS assay, Ca2+ measurements, RNA-seq, and conserved across Drosophila model\",\n      \"pmids\": [\"40705078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC16B functions as a lipid-responsive regulator in the liver. Hepatic Sec16b deficiency decreases VLDL secretion through mechanisms partially independent of MTP-mediated ApoB lipidation and COPII-mediated trafficking. SEC16B partially localizes at ER–lipid droplet (LD) contact sites and promotes LD expansion by facilitating targeting of ER proteins to LDs. Hepatic Sec16b suppression lowers serum lipids and reduces atherosclerotic lesion size in Ldlr-null mice.\",\n      \"method\": \"Hepatic conditional knockout, VLDL secretion assay, ER–LD contact site imaging, MTP inhibitor comparison, atherosclerosis mouse model (Ldlr-null)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — liver-specific KO with multiple mechanistic readouts (VLDL secretion, LD contact sites, in vivo atherosclerosis), multiple orthogonal methods\",\n      \"pmids\": [\"42030462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC16B acts as a tissue-selective modulator of COPII machinery in the liver, acting as a molecular brake to fine-tune COPII condensation for lipoprotein (APOB-containing) export. Hepatic deletion of SEC16B markedly reduces circulating APOB, triglycerides, and cholesterol, and protects against atherosclerosis and cardiac dysfunction. SEC16B expression is regulated by HNF4A.\",\n      \"method\": \"Hepatic knockout mouse model, integrative bioinformatics, AI-driven COPII condensation prediction, UK Biobank mining, atherosclerosis and cardiac function assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined molecular mechanism (COPII modulation), multiple in vivo phenotypic readouts, transcription factor regulation identified\",\n      \"pmids\": [\"42032080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC16B is a scaffold protein at ER exit sites that modulates COPII vesicle assembly for export of diverse cargoes including procollagen, APOB-containing lipoproteins (VLDL and chylomicrons), and peroxisomal biogenesis factors (Pex16/Pex3); it also localizes at ER–lipid droplet contact sites to promote lipid droplet expansion, is transcriptionally induced by ER stress via XBP1/ATF4, and in pancreatic beta cells supports cholinergic-driven Ca2+ influx and glucose-stimulated insulin secretion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC16B is a scaffold protein at ER exit sites that organizes COPII vesicle assembly for the export of diverse cargoes, including peroxisomal biogenesis factors (Pex16, Pex3), type I procollagen, and large APOB-containing lipoproteins (chylomicrons and VLDL), with its C-terminal domain conferring functions distinct from the paralog SEC16A [PMID:21768384, PMID:22279616, PMID:36916446, PMID:36796587]. In the liver, SEC16B fine-tunes COPII condensation to calibrate lipoprotein export, is transcriptionally regulated by HNF4A, and additionally localizes to ER–lipid droplet contact sites where it promotes lipid droplet expansion; hepatic deletion markedly lowers circulating APOB, triglycerides, and cholesterol and protects against atherosclerosis [PMID:42030462, PMID:42032080]. SEC16B is transcriptionally induced by ER stress through XBP1- and ATF4-responsive elements in its promoter and first intron [PMID:32815086], and in pancreatic beta cells it supports cholinergic signaling and Ca²⁺-dependent glucose-stimulated insulin secretion [PMID:40705078]. A homozygous loss-of-function SEC16B mutation causes osteogenesis imperfecta through impaired procollagen ER export [PMID:36916446].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that SEC16B is a non-redundant COPII scaffold at ER exit sites resolved the question of whether the two mammalian Sec16 paralogs serve overlapping or distinct functions, and revealed a specific role for SEC16B in ER-to-peroxisome trafficking of Pex16 and Pex3.\",\n      \"evidence\": \"RNAi knockdown, overexpression, rescue with RNAi-resistant construct, FRAP, and domain-deletion analysis in mammalian cells\",\n      \"pmids\": [\"21768384\", \"22279616\", \"22355596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which the SEC16B C-terminal domain specifically recognizes peroxisomal cargo is unknown\",\n        \"Whether SEC16B interacts directly with Pex16/Pex3 or acts indirectly through COPII components was not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying ER stress-responsive regulatory elements (UPRE and ATF4-binding site) in the SEC16B locus established that SEC16B expression is transcriptionally upregulated during the unfolded protein response, linking ER proteostasis to COPII capacity.\",\n      \"evidence\": \"Microarray, RT-PCR, and luciferase reporter assays with XBP1 and ATF4 in Neuro2a cells\",\n      \"pmids\": [\"32815086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of ER stress-induced SEC16B upregulation on COPII trafficking throughput was not measured\",\n        \"Whether the UPRE and ATF4 elements are conserved across species or cell types was not examined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that a homozygous SEC16B missense mutation causes osteogenesis imperfecta, with procollagen accumulation in the ER rescued by wild-type SEC16B, proved that SEC16B is essential for large-cargo ER export in humans and linked it to a Mendelian disease.\",\n      \"evidence\": \"Patient fibroblast analysis with immunofluorescence, ER trafficking assays, and wild-type rescue transfection\",\n      \"pmids\": [\"36916446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How SEC16B enables packaging of oversized procollagen into COPII carriers is mechanistically unresolved\",\n        \"Whether other collagen types or large ECM cargoes are similarly affected was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Intestinal-specific Sec16b knockout demonstrated that SEC16B is required for apoB lipidation and chylomicron secretion, establishing it as a rate-limiting factor in dietary lipid absorption and a contributor to diet-induced obesity.\",\n      \"evidence\": \"Conditional intestinal knockout mice with acute lipid challenge, fasting/HFD refeeding, and serum triglyceride measurements\",\n      \"pmids\": [\"36796587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SEC16B directly participates in pre-chylomicron transport vesicle formation or acts upstream on apoB lipidation was not resolved\",\n        \"Sex-specific protection from obesity (female mice) was not mechanistically explained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Sec16b deletion in pancreatic beta cells revealed an unexpected role in glucose-stimulated insulin secretion via cholinergic signaling and Ca²⁺ influx, extending SEC16B function beyond ER export scaffolding to endocrine cell physiology.\",\n      \"evidence\": \"Conditional knockout mice, GSIS assays, intracellular Ca²⁺ measurements, islet RNA-seq, and Drosophila RNAi epistasis\",\n      \"pmids\": [\"40705078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular link between SEC16B and cholinergic receptor surface expression or signaling is undefined\",\n        \"Whether the insulin secretion defect reflects impaired COPII-mediated trafficking of specific ion channels or receptors was not determined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Hepatic Sec16b studies revealed a dual mechanism: SEC16B acts as a molecular brake fine-tuning COPII condensation for APOB-lipoprotein export and also localizes to ER–lipid droplet contact sites to promote LD expansion, with hepatic deletion reducing serum lipids and atherosclerosis.\",\n      \"evidence\": \"Hepatic conditional knockout mice, VLDL secretion assays, ER–LD contact site imaging, atherosclerosis models (Ldlr-null), HNF4A transcriptional regulation, and AI-driven COPII condensation modeling\",\n      \"pmids\": [\"42030462\", \"42032080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for SEC16B's brake function on COPII condensation lacks experimental validation\",\n        \"How SEC16B is targeted to ER–LD contact sites and whether it interacts with known LD-tethering machinery is unknown\",\n        \"Long-term metabolic consequences of hepatic SEC16B loss remain to be assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of SEC16B's distinct C-terminal domain, its mechanism for modulating COPII condensate dynamics, and the molecular pathway linking it to cholinergic signaling in beta cells remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of SEC16B or its COPII interaction interfaces exists\",\n        \"Whether SEC16B directly contacts APOB or acts solely through COPII remodeling is unresolved\",\n        \"Cell-type-specific roles beyond intestine, liver, and beta cells are largely unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"COPII coat\"\n    ],\n    \"partners\": [\n      \"SEC16A\",\n      \"PEX16\",\n      \"PEX3\",\n      \"APOB\",\n      \"HNF4A\",\n      \"XBP1\",\n      \"ATF4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}