Affinage

SEC16B

Protein transport protein Sec16B · UniProt Q96JE7

Length
1060 aa
Mass
116.6 kDa
Annotated
2026-06-10
23 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 Medium

    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)

    PMID:16211248 PMID:16676356 PMID:19214710

    Open questions at the time
    • 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
  2. 2011 High

    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

    PMID:21768384 PMID:22279616 PMID:22355596

    Open questions at the time
    • 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
  3. 2020 Medium

    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

    PMID:32815086

    Open questions at the time
    • Functional consequence of stress-induced SEC16B upregulation for trafficking not tested
    • Direct binding of XBP1s/ATF4 to the identified elements not confirmed in vivo
  4. 2023 High

    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

    PMID:36796587 PMID:36916446

    Open questions at the time
    • 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
  5. 2025 High

    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

    PMID:40705078

    Open questions at the time
    • 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
  6. 2026 High

    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

    PMID:42030462 PMID:42032080

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 2 GO:0005811 lipid droplet 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
PEX16PEX3
Complex memberships
COPII coat

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. Overexpression, immunofluorescence localization, RNAi knockdown Scientific reports Medium 22355596
2011 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. RNAi knockdown, overexpression, rescue experiment, immunofluorescence, Western blot Proceedings of the National Academy of Sciences of the United States of America High 21768384
2011 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. Domain deletion analysis, overexpression, localization studies Cellular logistics Medium 22279616
2023 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. Intestinal knockout mouse model, acute oil challenge, fasting/refeeding assays, biochemical and imaging analyses Molecular metabolism High 36796587
2023 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. Patient fibroblast analysis, wild-type SEC16B rescue transfection, ER stress assays, autophagosome imaging EMBO molecular medicine Medium 36916446
2020 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. Microarray analysis, luciferase reporter assay, ER stress induction (thapsigargin, brefeldin A), sXBP1 overexpression Molecular and cellular biochemistry Medium 32815086
2025 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. Sec16b knockout mouse model, Drosophila RNAi knockdown, glucose and insulin tolerance tests, immunostaining, glucose-stimulated insulin secretion assays, RNA-seq of pancreatic islets Diabetologia High 40705078
2026 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. Hepatic knockout mouse model, VLDL secretion assays, lipid droplet imaging, ER-LD contact site localization, atherosclerosis model (Ldlr null mice) The Journal of clinical investigation High 42030462
2026 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. Hepatic knockout mouse model, integrative bioinformatics, AI-driven structural prediction, UK Biobank data mining, atherosclerosis model The EMBO journal High 42032080
2009 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. Yeast one-hybrid system, immunocytochemistry, Western blot, PKC signaling inhibitor experiments Molecular and cellular biochemistry Medium 19214710
2006 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. Luciferase reporter assay with wild-type and deletion constructs, kinase/phosphatase inhibitor treatment, stable transfection Journal of cellular biochemistry Medium 16676356
2005 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. Immunocytochemistry, Western blot fractionation, stable transfection International journal of molecular medicine Low 16211248
2022 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. Stable overexpression, colony formation assay, Western blot for signaling components, nuclear translocation assay Life sciences Low 35853523

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. Journal of human genetics 103 19851340
2011 Sec16B is involved in the endoplasmic reticulum export of the peroxisomal membrane biogenesis factor peroxin 16 (Pex16) in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 74 21768384
2015 Genetic variations in SEC16B, MC4R, MAP2K5 and KCTD15 were associated with childhood obesity and interacted with dietary behaviors in Chinese school-age population. Gene 37 25637721
2014 Association study of common polymorphisms in MSRA, TFAP2B, MC4R, NRXN3, PPARGC1A, TMEM18, SEC16B, HOXB5 and OLFM4 genes with obesity-related traits among Portuguese children. Journal of human genetics 34 24670271
2009 Novel protein RGPR-p117: its role as the regucalcin gene transcription factor. Molecular and cellular biochemistry 28 19214710
2011 Characterization of human Sec16B: indications of specialized, non-redundant functions. Scientific reports 26 22355596
2018 Genetic variants in SEC16B are associated with body composition in black South Africans. Nutrition & diabetes 23 30026463
2023 Intestinal SEC16B modulates obesity by regulating chylomicron metabolism. Molecular metabolism 18 36796587
2006 Overexpression of RGPR-p117 enhances regucalcin gene promoter activity in cloned normal rat kidney proximal tubular epithelial cells: involvement of TTGGC motif. Journal of cellular biochemistry 15 16676356
2023 Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress. EMBO molecular medicine 14 36916446
2005 Nuclear localization of a novel protein, RGPR-p117, in cloned normal rat kidney proximal tubular epithelial cells. International journal of molecular medicine 13 16211248
2011 Dual function of Sec16B: Endoplasmic reticulum-derived protein secretion and peroxisome biogenesis in mammalian cells. Cellular logistics 9 22279616
2020 Transcriptional regulation of the ER stress-inducible gene Sec16B in Neuro2a cells. Molecular and cellular biochemistry 5 32815086
2007 Overexpression of RGPR-p117 induces the decrease in protein and DNA contents in cloned normal rat kidney proximal tubular epithelial NRK52E cells. International journal of molecular medicine 5 17549392
2025 Overexpression of RGPR-p117 reveals anticancer effects by regulating multiple signaling pathways in bone metastatic human breast cancer MDA-MB-231 cells. IUBMB life 3 39780531
2022 The overexpressed transcription factor RGPR-p117 suppresses the proliferation of normal rat kidney proximal tubular epithelial NRK-52E cells: Involvement of diverse signaling pathways. Life sciences 3 35835253
2016 [Association between SEC16B polymorphisms and body mass index variation or risk of obesity: a Meta-analysis]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 3 27655580
2021 Female-Specific Susceptibility Locus in BOC and SEC16B are Associated with Adolescent Idiopathic Scoliosis. Spine 2 33958541
2025 Identification of SEC16B as a novel regulator of glucose homeostasis. Diabetologia 1 40705078
2025 Single-Cell RNA Sequencing Reveals the Critical Role of SEC16B in Lung Metastasis of Osteosarcoma. FASEB bioAdvances 1 40735296
2025 The advanced role of the transcription factor RGPR-p117 in cell regulation: Its involvement in transcription, cell growth, and lipid metabolism. International journal of biological macromolecules 1 40907915
2026 Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion. The Journal of clinical investigation 0 42030462
2026 Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export. The EMBO journal 0 42032080

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