{"gene":"SEC16B","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2011,"finding":"Sec16B localizes to ER exit sites (transitional ER) and acts as a scaffold for COPII coat assembly, defining ER exit sites in mammalian cells. Unlike Sec16A, overexpressed Sec16B targets to the entire ER membrane rather than remaining cytosolic.","method":"Overexpression, immunofluorescence localization, RNAi knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional characterization, single lab, multiple imaging methods","pmids":["22355596"],"is_preprint":false},{"year":2011,"finding":"Sec16B, but not Sec16A, is required for ER-to-peroxisome transport of peroxisomal membrane biogenesis factors Pex16 and Pex3 in mammalian cells. Knockdown of Sec16B by RNAi altered peroxisome morphology and inhibited Pex16 transport from the ER to peroxisomes; these phenotypes were rescued by RNAi-resistant Sec16B.","method":"RNAi knockdown, overexpression, rescue experiment, immunofluorescence, Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with specific cellular phenotype, rescue experiment with RNAi-resistant construct, multiple orthogonal methods in one study","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 transporting peroxisomal biogenesis factors from the ER to peroxisomes, and this function occurs at ER areas other than canonical ER exit sites.","method":"Domain deletion analysis, overexpression, localization studies","journal":"Cellular logistics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readout, single lab, supported by companion PNAS paper","pmids":["22279616"],"is_preprint":false},{"year":2023,"finding":"Intestinal SEC16B is required for dietary lipid absorption and chylomicron secretion in mice. Intestinal-specific knockout of Sec16b impaired ApoB lipidation and chylomicron secretion, resulting in reduced postprandial serum triglyceride output and protection from high-fat diet-induced obesity, particularly in female mice.","method":"Intestinal knockout mouse model, acute oil challenge, fasting/refeeding assays, biochemical and imaging analyses","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with defined molecular mechanism (impaired ApoB lipidation and chylomicron secretion), multiple physiological assays, in vivo model","pmids":["36796587"],"is_preprint":false},{"year":2023,"finding":"A homozygous missense mutation in SEC16B causes accumulation of type I procollagen in the ER and a general ER trafficking defect, leading to ER stress, enhanced autophagosome formation, and increased apoptosis in patient fibroblasts. Transfection of wild-type SEC16B into patient cells rescued collagen trafficking. The defect was due to reduced SEC16B expression rather than altered protein function.","method":"Patient fibroblast analysis, wild-type SEC16B rescue transfection, ER stress assays, autophagosome imaging","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cells with rescue experiment and multiple readouts, single lab","pmids":["36916446"],"is_preprint":false},{"year":2020,"finding":"Sec16B is an ER stress-inducible gene regulated via a functional unfolded protein response element (UPRE) in its promoter that responds to ER stress inducers and spliced XBP1 (sXBP1) overexpression. A unique ATF4-responsive sequence within the first intron also regulates Sec16B transcription.","method":"Microarray analysis, luciferase reporter assay, ER stress induction (thapsigargin, brefeldin A), sXBP1 overexpression","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with defined regulatory elements, multiple ER stress inducers tested, single lab","pmids":["32815086"],"is_preprint":false},{"year":2025,"finding":"SEC16B deficiency in mice impairs glucose homeostasis by reducing glucose-stimulated insulin secretion in pancreatic beta cells, through downregulation of cholinergic signaling and compromised intracellular Ca2+ influx. This function is conserved, as dSec16 knockdown in Drosophila also triggers glucose intolerance.","method":"Sec16b knockout mouse model, Drosophila RNAi knockdown, glucose and insulin tolerance tests, immunostaining, glucose-stimulated insulin secretion assays, RNA-seq of pancreatic islets","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two species (mouse and Drosophila), mechanistic pathway identified (cholinergic signaling, Ca2+ influx), multiple orthogonal assays","pmids":["40705078"],"is_preprint":false},{"year":2026,"finding":"Hepatic SEC16B promotes VLDL secretion and lipid droplet (LD) expansion to maintain lipid homeostasis. SEC16B partially localizes at ER-LD contact sites and facilitates targeting of ER proteins to LDs. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion through mechanisms at least partially independent of MTP-mediated ApoB lipidation and COPII-mediated trafficking. Suppression of Sec16b reduces atherosclerotic lesion size in Ldlr null mice.","method":"Hepatic knockout mouse model, VLDL secretion assays, lipid droplet imaging, ER-LD contact site localization, atherosclerosis model (Ldlr null mice)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with multiple mechanistic readouts, ER-LD contact site localization, in vivo atherosclerosis model, multiple orthogonal methods","pmids":["42030462"],"is_preprint":false},{"year":2026,"finding":"SEC16B is a tissue-selective modulator of the COPII machinery critical for efficient secretion of APOB-containing lipoproteins in the liver. SEC16B acts as a molecular brake to fine-tune COPII condensation for lipoprotein export. Hepatic deletion of SEC16B in mice markedly reduces circulating APOB, triglycerides and cholesterol, and confers protection against atherosclerosis and cardiac dysfunction. SEC16B expression is regulated in an HNF4A-dependent manner.","method":"Hepatic knockout mouse model, integrative bioinformatics, AI-driven structural prediction, UK Biobank data mining, atherosclerosis model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with defined molecular mechanism (COPII condensation modulation), multiple disease phenotypes validated in vivo, replicated across two independent 2026 studies","pmids":["42032080"],"is_preprint":false},{"year":2009,"finding":"RGPR-p117 (SEC16B) was identified as a transcription factor that binds the TTGGC(N)6CC nuclear factor I consensus motif in the regucalcin gene promoter region, using a yeast one-hybrid system. It translocates from cytoplasm to nucleus via protein kinase C signaling following hormonal stimulation, and phosphorylated RGPR-p117 enhances regucalcin mRNA expression.","method":"Yeast one-hybrid system, immunocytochemistry, Western blot, PKC signaling inhibitor experiments","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast one-hybrid binding assay plus signaling inhibitor experiments, single lab, multiple methods","pmids":["19214710"],"is_preprint":false},{"year":2006,"finding":"RGPR-p117 (SEC16B) overexpression enhances regucalcin gene promoter activity in NRK52E cells via the TTGGC motif at the -523/-435 region. This enhancing effect requires phosphorylation/dephosphorylation events mediated by multiple kinases including PKC, PI3K, and tyrosine kinases.","method":"Luciferase reporter assay with wild-type and deletion constructs, kinase/phosphatase inhibitor treatment, stable transfection","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with specific deletion mutants identifying required motif, multiple inhibitor conditions, single lab","pmids":["16676356"],"is_preprint":false},{"year":2005,"finding":"RGPR-p117 (SEC16B) localizes to both cytoplasm and nucleus in NRK52E kidney cells, and its nuclear localization is accompanied by stimulation of regucalcin mRNA expression upon overexpression.","method":"Immunocytochemistry, Western blot fractionation, stable transfection","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (immunocytochemistry), limited functional follow-up","pmids":["16211248"],"is_preprint":false},{"year":2022,"finding":"RGPR-p117 (SEC16B) overexpression in NRK-52E cells suppresses cell proliferation by decreasing levels of Ras, PI3K, Akt, MAPK, and mTOR while increasing p53, Rb, p21, and regucalcin. RGPR-p117 overexpression also blocks proliferation stimulated by calcium entry agonist (Bay K 8644) and PKC activator (PMA), and increases nuclear translocation of RGPR-p117.","method":"Stable overexpression, colony formation assay, Western blot for signaling components, nuclear translocation assay","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with Western blot readouts, single lab, no direct mechanistic experiments on specific pathway interactions","pmids":["35853523"],"is_preprint":false}],"current_model":"SEC16B (also known as RGPR-p117/Sec16S) is a scaffold protein at ER exit sites that organizes COPII vesicle formation; it has specialized roles distinct from SEC16A, including facilitating ER-to-peroxisome transport of peroxins (Pex16, Pex3) via its unique C-terminal region, promoting intestinal chylomicron secretion and ApoB lipidation for dietary lipid absorption, driving hepatic VLDL secretion and lipid droplet expansion at ER-LD contact sites by modulating COPII condensation, and supporting glucose-stimulated insulin secretion in pancreatic beta cells through cholinergic signaling and Ca2+ influx; additionally, as RGPR-p117 it acts as a nuclear transcription factor binding the TTGGC motif to regulate regucalcin gene expression via PKC/PI3K-dependent phosphorylation."},"narrative":{"mechanistic_narrative":"SEC16B is a scaffold protein of endoplasmic reticulum exit sites that organizes COPII coat assembly and defines transitional ER in mammalian cells, distinguishing itself from SEC16A by targeting the entire ER membrane when overexpressed [PMID:22355596]. Beyond canonical secretory traffic, SEC16B has a specialized, C-terminally encoded role—absent in SEC16A—in delivering the peroxisomal membrane biogenesis factors Pex16 and Pex3 from the ER to peroxisomes, acting at ER regions distinct from canonical exit sites [PMID:21768384, PMID:22279616]. SEC16B is a tissue-selective regulator of lipoprotein secretion: intestinal SEC16B is required for ApoB lipidation and chylomicron output during dietary lipid absorption [PMID:36796587], while hepatic SEC16B promotes VLDL secretion and lipid droplet expansion, localizing in part to ER–lipid droplet contact sites and acting as a molecular brake that fine-tunes COPII condensation for APOB-containing lipoprotein export under HNF4A-dependent control [PMID:42030462, PMID:42032080]; its hepatic loss lowers circulating lipids and protects against atherosclerosis [PMID:42030462, PMID:42032080]. SEC16B additionally supports glucose-stimulated insulin secretion in pancreatic beta cells through cholinergic signaling and intracellular Ca2+ influx, a function conserved in Drosophila [PMID:40705078]. A homozygous missense mutation that reduces SEC16B expression causes ER accumulation of type I procollagen, a general ER trafficking defect, ER stress, and apoptosis in patient fibroblasts, rescued by wild-type SEC16B [PMID:36916446]; consistent with this, SEC16B is itself an ER stress-inducible gene driven by a UPRE and an ATF4-responsive element [PMID:32815086]. A separate body of work characterizes SEC16B (as RGPR-p117) as a nuclear factor that binds the TTGGC motif in the regucalcin promoter and enhances regucalcin transcription following PKC/PI3K-dependent phosphorylation [PMID:19214710, PMID:16676356].","teleology":[{"year":2009,"claim":"Before the secretory role was defined, work on RGPR-p117 established a nuclear transcription-factor activity, showing it binds a specific promoter motif and is regulated by signaling-driven nuclear translocation.","evidence":"Yeast one-hybrid binding, immunocytochemistry, and PKC inhibitor experiments in kidney cells (consolidating earlier 2005/2006 RGPR-p117 reporter work)","pmids":["19214710","16676356","16211248"],"confidence":"Medium","gaps":["Direct DNA-binding by purified protein and in vivo occupancy not shown","Relationship between the nuclear transcription-factor role and the ER scaffold function not reconciled","No structural basis for TTGGC motif recognition"]},{"year":2011,"claim":"Established SEC16B as a COPII scaffold defining mammalian ER exit sites and revealed a SEC16A-independent, C-terminus-dependent role in ER-to-peroxisome transport of Pex16 and Pex3.","evidence":"Overexpression/immunofluorescence localization plus RNAi knockdown with RNAi-resistant rescue and domain-deletion analysis in mammalian cells","pmids":["22355596","21768384","22279616"],"confidence":"High","gaps":["Mechanism by which the unique C-terminus directs peroxin cargo not defined","Direct interaction with COPII components or peroxins not biochemically mapped","Whether peroxisome transport uses COPII vesicles or a distinct carrier unresolved"]},{"year":2020,"claim":"Connected SEC16B to the secretory stress response by showing its transcription is induced by ER stress through a UPRE and an ATF4-responsive element.","evidence":"Microarray, luciferase reporter assays with defined regulatory elements, and ER stress induction plus sXBP1 overexpression","pmids":["32815086"],"confidence":"Medium","gaps":["Functional consequence of stress-induced SEC16B upregulation for trafficking not tested","Direct binding of XBP1s/ATF4 to the identified elements not confirmed in vivo"]},{"year":2023,"claim":"Demonstrated tissue-specific physiological roles: intestinal SEC16B drives chylomicron secretion and dietary lipid absorption, while a human loss-of-expression mutation produces a general ER trafficking and procollagen secretion defect.","evidence":"Intestinal-specific knockout mice with lipid challenge assays, and patient fibroblast analysis with wild-type rescue","pmids":["36796587","36916446"],"confidence":"High","gaps":["Clinical syndrome and inheritance from the missense mutation not fully delineated","Molecular link between SEC16B and ApoB lipidation step not resolved","Sex-biased intestinal phenotype mechanism unexplained"]},{"year":2025,"claim":"Extended SEC16B function to metabolic homeostasis by showing it is required for glucose-stimulated insulin secretion via cholinergic signaling and Ca2+ influx, with conservation across mouse and Drosophila.","evidence":"Sec16b knockout mice and dSec16 Drosophila RNAi, glucose/insulin tolerance tests, GSIS assays, and islet RNA-seq","pmids":["40705078"],"confidence":"High","gaps":["How an ER scaffold modulates cholinergic signaling and Ca2+ channels mechanistically unclear","Whether the insulin phenotype reflects secretory trafficking or a separate pathway not separated"]},{"year":2026,"claim":"Resolved hepatic SEC16B as a molecular brake on COPII condensation that fine-tunes APOB-lipoprotein/VLDL secretion and lipid droplet expansion, establishing it as an atherosclerosis-relevant, HNF4A-regulated target.","evidence":"Two independent hepatic knockout mouse studies with VLDL secretion assays, ER-LD contact site imaging, AI structural prediction, UK Biobank mining, and atherosclerosis models in Ldlr-null mice","pmids":["42030462","42032080"],"confidence":"High","gaps":["Molecular basis of COPII condensation modulation by SEC16B not structurally defined","MTP/COPII-independent component of VLDL secretion mechanistically unexplained","Direct role at ER-LD contact sites versus indirect effect not separated"]},{"year":null,"claim":"How the same protein operates as an ER-exit-site COPII scaffold and as a nuclear transcription factor, and whether these activities are mechanistically linked, remains unresolved.","evidence":"No timeline study directly bridges the secretory and transcriptional functions","pmids":[],"confidence":"Low","gaps":["No experiment connects nuclear RGPR-p117 activity to ER trafficking","Domain or isoform basis for dual localization not defined","No structural model of the full-length protein in either role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,3,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,6,7,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,10]}],"complexes":["COPII coat"],"partners":["PEX16","PEX3"],"other_free_text":[]}},"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":103,"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":74,"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":26,"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":23,"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":18,"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 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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 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Sea","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.02.685776","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14523,"output_tokens":3270,"usd":0.04631,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10812,"output_tokens":3128,"usd":0.06613,"stage2_stop_reason":"end_turn"},"total_usd":0.11244,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Sec16B localizes to ER exit sites (transitional ER) and acts as a scaffold for COPII coat assembly, defining ER exit sites in mammalian cells. Unlike Sec16A, overexpressed Sec16B targets to the entire ER membrane rather than remaining cytosolic.\",\n      \"method\": \"Overexpression, immunofluorescence localization, RNAi knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional characterization, single lab, multiple imaging methods\",\n      \"pmids\": [\"22355596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sec16B, but not Sec16A, is required for ER-to-peroxisome transport of peroxisomal membrane biogenesis factors Pex16 and Pex3 in mammalian cells. Knockdown of Sec16B by RNAi altered peroxisome morphology and inhibited Pex16 transport from the ER to peroxisomes; these phenotypes were rescued by RNAi-resistant Sec16B.\",\n      \"method\": \"RNAi knockdown, overexpression, rescue experiment, immunofluorescence, Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with specific cellular phenotype, rescue experiment with RNAi-resistant construct, multiple orthogonal methods in one study\",\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 transporting peroxisomal biogenesis factors from the ER to peroxisomes, and this function occurs at ER areas other than canonical ER exit sites.\",\n      \"method\": \"Domain deletion analysis, overexpression, localization studies\",\n      \"journal\": \"Cellular logistics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readout, single lab, supported by companion PNAS paper\",\n      \"pmids\": [\"22279616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal SEC16B is required for dietary lipid absorption and chylomicron secretion in mice. Intestinal-specific knockout of Sec16b impaired ApoB lipidation and chylomicron secretion, resulting in reduced postprandial serum triglyceride output and protection from high-fat diet-induced obesity, particularly in female mice.\",\n      \"method\": \"Intestinal knockout mouse model, acute oil challenge, fasting/refeeding assays, biochemical and imaging analyses\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with defined molecular mechanism (impaired ApoB lipidation and chylomicron secretion), multiple physiological assays, in vivo model\",\n      \"pmids\": [\"36796587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous missense mutation in SEC16B causes accumulation of type I procollagen in the ER and a general ER trafficking defect, leading to ER stress, enhanced autophagosome formation, and increased apoptosis in patient fibroblasts. Transfection of wild-type SEC16B into patient cells rescued collagen trafficking. The defect was due to reduced SEC16B expression rather than altered protein function.\",\n      \"method\": \"Patient fibroblast analysis, wild-type SEC16B rescue transfection, ER stress assays, autophagosome imaging\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cells with rescue experiment and multiple readouts, single lab\",\n      \"pmids\": [\"36916446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sec16B is an ER stress-inducible gene regulated via a functional unfolded protein response element (UPRE) in its promoter that responds to ER stress inducers and spliced XBP1 (sXBP1) overexpression. A unique ATF4-responsive sequence within the first intron also regulates Sec16B transcription.\",\n      \"method\": \"Microarray analysis, luciferase reporter assay, ER stress induction (thapsigargin, brefeldin A), sXBP1 overexpression\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with defined regulatory elements, multiple ER stress inducers tested, single lab\",\n      \"pmids\": [\"32815086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC16B deficiency in mice impairs glucose homeostasis by reducing glucose-stimulated insulin secretion in pancreatic beta cells, through downregulation of cholinergic signaling and compromised intracellular Ca2+ influx. This function is conserved, as dSec16 knockdown in Drosophila also triggers glucose intolerance.\",\n      \"method\": \"Sec16b knockout mouse model, Drosophila RNAi knockdown, glucose and insulin tolerance tests, immunostaining, glucose-stimulated insulin secretion assays, RNA-seq of pancreatic islets\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two species (mouse and Drosophila), mechanistic pathway identified (cholinergic signaling, Ca2+ influx), multiple orthogonal assays\",\n      \"pmids\": [\"40705078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Hepatic SEC16B promotes VLDL secretion and lipid droplet (LD) expansion to maintain lipid homeostasis. SEC16B partially localizes at ER-LD contact sites and facilitates targeting of ER proteins to LDs. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion through mechanisms at least partially independent of MTP-mediated ApoB lipidation and COPII-mediated trafficking. Suppression of Sec16b reduces atherosclerotic lesion size in Ldlr null mice.\",\n      \"method\": \"Hepatic knockout mouse model, VLDL secretion assays, lipid droplet imaging, ER-LD contact site localization, atherosclerosis model (Ldlr null mice)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with multiple mechanistic readouts, ER-LD contact site localization, in vivo atherosclerosis model, multiple orthogonal methods\",\n      \"pmids\": [\"42030462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC16B is a tissue-selective modulator of the COPII machinery critical for efficient secretion of APOB-containing lipoproteins in the liver. SEC16B acts as a molecular brake to fine-tune COPII condensation for lipoprotein export. Hepatic deletion of SEC16B in mice markedly reduces circulating APOB, triglycerides and cholesterol, and confers protection against atherosclerosis and cardiac dysfunction. SEC16B expression is regulated in an HNF4A-dependent manner.\",\n      \"method\": \"Hepatic knockout mouse model, integrative bioinformatics, AI-driven structural prediction, UK Biobank data mining, atherosclerosis model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with defined molecular mechanism (COPII condensation modulation), multiple disease phenotypes validated in vivo, replicated across two independent 2026 studies\",\n      \"pmids\": [\"42032080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RGPR-p117 (SEC16B) was identified as a transcription factor that binds the TTGGC(N)6CC nuclear factor I consensus motif in the regucalcin gene promoter region, using a yeast one-hybrid system. It translocates from cytoplasm to nucleus via protein kinase C signaling following hormonal stimulation, and phosphorylated RGPR-p117 enhances regucalcin mRNA expression.\",\n      \"method\": \"Yeast one-hybrid system, immunocytochemistry, Western blot, PKC signaling inhibitor experiments\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast one-hybrid binding assay plus signaling inhibitor experiments, single lab, multiple methods\",\n      \"pmids\": [\"19214710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RGPR-p117 (SEC16B) overexpression enhances regucalcin gene promoter activity in NRK52E cells via the TTGGC motif at the -523/-435 region. This enhancing effect requires phosphorylation/dephosphorylation events mediated by multiple kinases including PKC, PI3K, and tyrosine kinases.\",\n      \"method\": \"Luciferase reporter assay with wild-type and deletion constructs, kinase/phosphatase inhibitor treatment, stable transfection\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with specific deletion mutants identifying required motif, multiple inhibitor conditions, single lab\",\n      \"pmids\": [\"16676356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RGPR-p117 (SEC16B) localizes to both cytoplasm and nucleus in NRK52E kidney cells, and its nuclear localization is accompanied by stimulation of regucalcin mRNA expression upon overexpression.\",\n      \"method\": \"Immunocytochemistry, Western blot fractionation, stable transfection\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (immunocytochemistry), limited functional follow-up\",\n      \"pmids\": [\"16211248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGPR-p117 (SEC16B) overexpression in NRK-52E cells suppresses cell proliferation by decreasing levels of Ras, PI3K, Akt, MAPK, and mTOR while increasing p53, Rb, p21, and regucalcin. RGPR-p117 overexpression also blocks proliferation stimulated by calcium entry agonist (Bay K 8644) and PKC activator (PMA), and increases nuclear translocation of RGPR-p117.\",\n      \"method\": \"Stable overexpression, colony formation assay, Western blot for signaling components, nuclear translocation assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with Western blot readouts, single lab, no direct mechanistic experiments on specific pathway interactions\",\n      \"pmids\": [\"35853523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC16B (also known as RGPR-p117/Sec16S) is a scaffold protein at ER exit sites that organizes COPII vesicle formation; it has specialized roles distinct from SEC16A, including facilitating ER-to-peroxisome transport of peroxins (Pex16, Pex3) via its unique C-terminal region, promoting intestinal chylomicron secretion and ApoB lipidation for dietary lipid absorption, driving hepatic VLDL secretion and lipid droplet expansion at ER-LD contact sites by modulating COPII condensation, and supporting glucose-stimulated insulin secretion in pancreatic beta cells through cholinergic signaling and Ca2+ influx; additionally, as RGPR-p117 it acts as a nuclear transcription factor binding the TTGGC motif to regulate regucalcin gene expression via PKC/PI3K-dependent phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC16B is a scaffold protein of endoplasmic reticulum exit sites that organizes COPII coat assembly and defines transitional ER in mammalian cells, distinguishing itself from SEC16A by targeting the entire ER membrane when overexpressed [#0]. Beyond canonical secretory traffic, SEC16B has a specialized, C-terminally encoded role—absent in SEC16A—in delivering the peroxisomal membrane biogenesis factors Pex16 and Pex3 from the ER to peroxisomes, acting at ER regions distinct from canonical exit sites [#1, #2]. SEC16B is a tissue-selective regulator of lipoprotein secretion: intestinal SEC16B is required for ApoB lipidation and chylomicron output during dietary lipid absorption [#3], while hepatic SEC16B promotes VLDL secretion and lipid droplet expansion, localizing in part to ER–lipid droplet contact sites and acting as a molecular brake that fine-tunes COPII condensation for APOB-containing lipoprotein export under HNF4A-dependent control [#7, #8]; its hepatic loss lowers circulating lipids and protects against atherosclerosis [#7, #8]. SEC16B additionally supports glucose-stimulated insulin secretion in pancreatic beta cells through cholinergic signaling and intracellular Ca2+ influx, a function conserved in Drosophila [#6]. A homozygous missense mutation that reduces SEC16B expression causes ER accumulation of type I procollagen, a general ER trafficking defect, ER stress, and apoptosis in patient fibroblasts, rescued by wild-type SEC16B [#4]; consistent with this, SEC16B is itself an ER stress-inducible gene driven by a UPRE and an ATF4-responsive element [#5]. A separate body of work characterizes SEC16B (as RGPR-p117) as a nuclear factor that binds the TTGGC motif in the regucalcin promoter and enhances regucalcin transcription following PKC/PI3K-dependent phosphorylation [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Before the secretory role was defined, work on RGPR-p117 established a nuclear transcription-factor activity, showing it binds a specific promoter motif and is regulated by signaling-driven nuclear translocation.\",\n      \"evidence\": \"Yeast one-hybrid binding, immunocytochemistry, and PKC inhibitor experiments in kidney cells (consolidating earlier 2005/2006 RGPR-p117 reporter work)\",\n      \"pmids\": [\"19214710\", \"16676356\", \"16211248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding by purified protein and in vivo occupancy not shown\", \"Relationship between the nuclear transcription-factor role and the ER scaffold function not reconciled\", \"No structural basis for TTGGC motif recognition\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established SEC16B as a COPII scaffold defining mammalian ER exit sites and revealed a SEC16A-independent, C-terminus-dependent role in ER-to-peroxisome transport of Pex16 and Pex3.\",\n      \"evidence\": \"Overexpression/immunofluorescence localization plus RNAi knockdown with RNAi-resistant rescue and domain-deletion analysis in mammalian cells\",\n      \"pmids\": [\"22355596\", \"21768384\", \"22279616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the unique C-terminus directs peroxin cargo not defined\", \"Direct interaction with COPII components or peroxins not biochemically mapped\", \"Whether peroxisome transport uses COPII vesicles or a distinct carrier unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SEC16B to the secretory stress response by showing its transcription is induced by ER stress through a UPRE and an ATF4-responsive element.\",\n      \"evidence\": \"Microarray, luciferase reporter assays with defined regulatory elements, and ER stress induction plus sXBP1 overexpression\",\n      \"pmids\": [\"32815086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of stress-induced SEC16B upregulation for trafficking not tested\", \"Direct binding of XBP1s/ATF4 to the identified elements not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated tissue-specific physiological roles: intestinal SEC16B drives chylomicron secretion and dietary lipid absorption, while a human loss-of-expression mutation produces a general ER trafficking and procollagen secretion defect.\",\n      \"evidence\": \"Intestinal-specific knockout mice with lipid challenge assays, and patient fibroblast analysis with wild-type rescue\",\n      \"pmids\": [\"36796587\", \"36916446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical syndrome and inheritance from the missense mutation not fully delineated\", \"Molecular link between SEC16B and ApoB lipidation step not resolved\", \"Sex-biased intestinal phenotype mechanism unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended SEC16B function to metabolic homeostasis by showing it is required for glucose-stimulated insulin secretion via cholinergic signaling and Ca2+ influx, with conservation across mouse and Drosophila.\",\n      \"evidence\": \"Sec16b knockout mice and dSec16 Drosophila RNAi, glucose/insulin tolerance tests, GSIS assays, and islet RNA-seq\",\n      \"pmids\": [\"40705078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER scaffold modulates cholinergic signaling and Ca2+ channels mechanistically unclear\", \"Whether the insulin phenotype reflects secretory trafficking or a separate pathway not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved hepatic SEC16B as a molecular brake on COPII condensation that fine-tunes APOB-lipoprotein/VLDL secretion and lipid droplet expansion, establishing it as an atherosclerosis-relevant, HNF4A-regulated target.\",\n      \"evidence\": \"Two independent hepatic knockout mouse studies with VLDL secretion assays, ER-LD contact site imaging, AI structural prediction, UK Biobank mining, and atherosclerosis models in Ldlr-null mice\",\n      \"pmids\": [\"42030462\", \"42032080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of COPII condensation modulation by SEC16B not structurally defined\", \"MTP/COPII-independent component of VLDL secretion mechanistically unexplained\", \"Direct role at ER-LD contact sites versus indirect effect not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protein operates as an ER-exit-site COPII scaffold and as a nuclear transcription factor, and whether these activities are mechanistically linked, remains unresolved.\",\n      \"evidence\": \"No timeline study directly bridges the secretory and transcriptional functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experiment connects nuclear RGPR-p117 activity to ER trafficking\", \"Domain or isoform basis for dual localization not defined\", \"No structural model of the full-length protein in either role\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\"COPII coat\"],\n    \"partners\": [\"PEX16\", \"PEX3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}