Affinage

SEC16A

Protein transport protein Sec16A · UniProt O15027

Round 2 corrected
Length
2357 aa
Mass
251.9 kDa
Annotated
2026-04-28
47 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEC16A is a large scaffolding protein that organizes endoplasmic reticulum exit sites (ERES) and serves as a master regulator of anterograde ER-to-Golgi transport. It is recruited to ER membranes in a Sar1-dependent manner and interacts with both inner (Sec23–Sec24) and outer (Sec13–Sec31) COPII coat complexes; depletion disorganizes ERES and delays secretory trafficking, while loss-of-function variants impede COPII assembly, induce ER stress, and in mice exacerbate cerulein-induced pancreatic inflammation and fibrosis (PMID:17428803, PMID:39119875). Beyond canonical COPII-dependent export, SEC16A functions as a RAB10 effector driving insulin-stimulated GLUT4 translocation via a non-canonical COPII subcomplex (PMID:27354378), mediates GRASP55-dependent unconventional secretion of CFTR downstream of IRE1α during ER stress (PMID:28067262), and is anchored at ERES by LRRK2, whose Parkinson's-disease-associated R1441C mutation disrupts this interaction and impairs ER-Golgi transport in neurons (PMID:25201882). SEC16A additionally stabilizes ER-associated ubiquitin ligases RNF183 and RNF152 through its central conserved domain, and a missense mutation in this domain causes neurological impairment in mice (PMID:29300766, PMID:41104514).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 High

    Establishing SEC16A as the mammalian ERES scaffold resolved how the two-layered COPII coat is spatially organized on ER membranes, showing that a single protein interacts with both inner and outer coat and that its loss disorganizes exit sites.

    Evidence Subcellular fractionation, binding assays with COPII components, siRNA knockdown and fluorescence microscopy in mammalian cells

    PMID:17428803

    Open questions at the time
    • Mechanism by which SEC16A is initially targeted to specific ER membrane domains remains unclear
    • Structural basis of SEC16A interactions with Sec23–Sec24 and Sec13–Sec31 not resolved
    • Whether SEC16A has catalytic activity or functions purely as a scaffold was not addressed
  2. 2014 High

    Demonstrating that LRRK2 anchors SEC16A at ERES and that the PD-associated R1441C mutation disrupts this interaction linked ERES organization to neurodegeneration and revealed how SEC16A retention at exit sites is regulated upstream.

    Evidence Reciprocal co-immunoprecipitation, co-localization imaging, domain-mutant analysis, and neuronal surface receptor trafficking assays

    PMID:25201882

    Open questions at the time
    • Direct binding interface between LRRK2 and SEC16A not mapped at residue level
    • Whether other kinases or GTPases can substitute for LRRK2 in anchoring SEC16A is unknown
  3. 2016 High

    Identifying SEC16A as a RAB10 effector for insulin-stimulated GLUT4 translocation revealed a non-canonical COPII function independent of the full canonical coat, broadening SEC16A's role beyond classical ER export.

    Evidence siRNA epistasis with individual COPII components, GLUT4 translocation assay, and co-localization imaging in adipocytes

    PMID:27354378

    Open questions at the time
    • Composition of the non-canonical SEC16A–SEC23A subcomplex not fully defined
    • Whether RAB10–SEC16A interaction is direct or mediated through an adaptor is unresolved
  4. 2017 High

    Showing that SEC16A mediates GRASP55-dependent unconventional secretion of CFTR downstream of IRE1α established SEC16A as a bifunctional scaffold operating in both canonical and Golgi-bypassing secretory routes during ER stress.

    Evidence siRNA knockdown screen, co-immunoprecipitation with GRASP55, CFTR secretion assay, and IRE1α inhibition

    PMID:28067262

    Open questions at the time
    • Cargo selectivity of the unconventional pathway beyond CFTR not characterized
    • Mechanism by which IRE1α signaling triggers SEC16A redistribution to the cell periphery is unknown
  5. 2018 Medium

    Mapping the central conserved domain (CCD) as the interface for stabilizing ER-associated ubiquitin ligases RNF183 and RNF152 extended SEC16A's function beyond vesicle coat organization to proteostasis regulation.

    Evidence Co-immunoprecipitation, domain deletion mapping, and degradation assays

    PMID:29300766

    Open questions at the time
    • Mechanism by which SEC16A shields these ligases from ERAD is not defined
    • Whether additional E3 ligases are stabilized by SEC16A's CCD is untested
    • Finding from a single laboratory awaits independent confirmation
  6. 2024 High

    Demonstrating that SEC16A loss-of-function variants impede COPII assembly and cause ER stress, and that Sec16a haploinsufficiency in mice exacerbates pancreatic inflammation and fibrosis, provided the first in vivo disease-relevant model linking SEC16A deficiency to organ pathology.

    Evidence CRISPR/Cas9-edited HEK293T cells, COPII assembly and secretion assays, ER stress markers, Sec16a+/- mouse model with cerulein-induced pancreatitis

    PMID:39119875

    Open questions at the time
    • Whether SEC16A variants contribute to human pancreatitis susceptibility requires clinical genetic studies
    • Cell-type-specific consequences of SEC16A deficiency beyond pancreatic acinar cells not explored
  7. 2025 Medium

    A knock-in mouse carrying a CCD missense mutation (L1551V) displayed neurological deficits including impaired learning/memory and neurodegeneration-associated clasping, establishing that even subtle disruption of the COPII-interacting domain has consequences for CNS function.

    Evidence CRISPR/Cas9 knock-in mouse model with behavioral testing (novel object recognition, fear conditioning, tail suspension)

    PMID:41104514

    Open questions at the time
    • Cellular mechanism linking CCD mutation to neurodegeneration not elucidated
    • Whether this mutation affects COPII assembly, ubiquitin ligase stabilization, or both is untested
    • Findings from a single mouse model line

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SEC16A coordinates its multiple scaffolding roles — canonical COPII assembly, non-canonical vesicle biogenesis, unconventional secretion, and ubiquitin ligase stabilization — through its distinct domains, and whether these functions are mutually exclusive or concurrent at the same ERES, remains unresolved.
  • No high-resolution structure of full-length SEC16A or its domain complexes exists
  • Post-translational modifications regulating switching between canonical and non-canonical functions are uncharacterized
  • In vivo tissue-specific requirements for SEC16A beyond pancreas and brain are largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 3 R-HSA-392499 Metabolism of proteins 2
Partners
GRASP55LRRK2RAB10RNF183SEC13SEC23ASEC24SEC31
Complex memberships
COPII coat

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Mammalian SEC16A (KIAA0310p/p250) is a homologue of yeast Sec16 that localizes to ER exit sites (ERES) and is recruited from the cytosol to ER membranes in a Sar1-dependent manner. It interacts with both the inner COPII layer (Sec23-Sec24) and outer layer (Sec13-Sec31) complexes. Depletion causes disorganization of ERES and delayed ER-to-Golgi protein transport. Subcellular fractionation, binding experiments, siRNA knockdown, fluorescence microscopy The Journal of biological chemistry High 17428803
2014 LRRK2 interacts and co-localizes with SEC16A and anchors it at ERES. Loss of LRRK2 disperses SEC16A from ERES and impairs ER export. In neurons, LRRK2 and SEC16A co-localize at dendritic ERES and regulate activity-dependent surface targeting of glutamate receptors. The PD-associated LRRK2 R1441C GTPase-domain mutation disrupts the LRRK2-SEC16A interaction and impairs ER-Golgi transport; LRRK2 kinase activity is not required. Co-immunoprecipitation, co-localization imaging, siRNA knockdown, domain-mutant analysis, neuronal surface receptor trafficking assays The EMBO journal High 25201882
2016 SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 translocation to the plasma membrane in adipocytes. Insulin augments colocalization of SEC16A with RAB10 at a perinuclear recycling endosome/TGN compartment, and SEC16A knockdown phenocopies RAB10 knockdown. This function is independent of canonical COPII coat assembly (SEC13, SEC23B, SEC31 not required), but SEC23A is involved, suggesting a non-canonical COPII subcomplex role. siRNA knockdown, co-localization imaging, GLUT4 translocation assay, insulin stimulation, epistasis with COPII component knockdowns The Journal of cell biology High 27354378
2017 SEC16A plays a critical role in unconventional (Golgi-bypassing) secretion of CFTR and ΔF508-CFTR. During ER-to-Golgi blockade or ER stress, SEC16A is redistributed to the cell periphery and associates with GRASP55. IRE1α-mediated signaling acts as an upstream regulator of SEC16A redistribution during unconventional secretion. Knockdown of SEC16A, but not other COPII components, abolishes this unconventional pathway. siRNA knockdown screen, co-immunoprecipitation, immunofluorescence, CFTR secretion assay, IRE1α inhibition Scientific reports High 28067262
2017 SEC16A was identified as an interactor of the scaffolding protein Nbeal2 in platelets/megakaryocytes, validated by reverse immunoprecipitation and proximity ligation assay. Affinity purification mass spectrometry (interactome), reverse immunoprecipitation, proximity ligation assay Blood Medium 29187380
2018 SEC16A interacts with the ubiquitin ligase RNF183 through its central conserved domain (CCD). SEC16A is not a substrate for RNF183 but stabilizes RNF183 against ERAD-mediated degradation. SEC16A similarly stabilizes the lysosomal ubiquitin ligase RNF152, indicating a broader role in regulating ubiquitin ligase protein stability and localization. Co-immunoprecipitation, domain deletion mapping, degradation assays, co-localization imaging PloS one Medium 29300766
2024 Loss-of-function SEC16A variants (including frameshift and missense) disrupt COPII complex formation, impede secretory protein vesicle trafficking from the ER, and induce ER stress due to protein overload, as shown in CRISPR/Cas9-edited HEK293T cells. Sec16a+/- mice show impaired zymogen secretion, exacerbated ER stress, and heightened pancreatic inflammation and fibrosis upon cerulein challenge. CRISPR/Cas9 knockout cell lines, COPII assembly assay, secretion trafficking assay, ER stress markers, mouse model with pancreatitis challenge Advanced science High 39119875
2025 SEC16A is depleted of VLC-ceramide trafficking from the ER to the Golgi upon cholesterol depletion. Depletion of SEC16A abolishes the increased synthesis of very-long-chain sphingomyelin that is induced by cholesterol depletion, establishing SEC16A/COPII as a rate-limiting node in ER-to-Golgi ceramide transport and organelle membrane homeostasis. siRNA knockdown of SEC16A, sphingolipid metabolic flux analysis, sphingolipid trafficking assay bioRxivpreprint Medium bio_10.1101_2025.02.12.637879
2025 The head domain of the Golgi vesicle tether p115 (USO1) binds directly to a conserved motif in the unstructured N-terminal region of SEC16A. Structural prediction and deletion mapping define the interaction surface, and p115 mutations that block this motif reduce secretion efficiency, suggesting p115 bridges early Golgi to ERES via SEC16A. Direct binding assay, deletion mapping, structural prediction, secretion efficiency assay with p115 mutants bioRxivpreprint Medium bio_10.1101_2025.10.16.682774
2025 A knock-in mouse model carrying the Sec16a L1551V mutation (corresponding to human L1536V in the conserved central core domain involved in COPII assembly) displays neurological impairment: homozygous mice show deficits in novel object recognition and fear-conditioned learning/memory, and limb clasping behavior associated with neurodegeneration. CRISPR/Cas9 knock-in mouse model, behavioral testing (novel object recognition, cued fear conditioning, tail suspension) Animal models and experimental medicine Medium 41104514

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 1362 16751776
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2011 Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature genetics 1078 21297633
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
1993 The p250 subunit of native TATA box-binding factor TFIID is the cell-cycle regulatory protein CCG1. Nature 185 8450888
2007 Mammalian Sec16/p250 plays a role in membrane traffic from the endoplasmic reticulum. The Journal of biological chemistry 67 17428803
2014 Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export. The EMBO journal 65 25201882
2016 SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking in adipocytes. The Journal of cell biology 48 27354378
2001 Opposing effects of molecular volume and charge at the hyperekplexia site alpha 1(P250) govern glycine receptor activation and desensitization. The Journal of biological chemistry 41 11395484
2017 Sec16A is critical for both conventional and unconventional secretion of CFTR. Scientific reports 35 28067262
2017 Nbeal2 interacts with Dock7, Sec16a, and Vac14. Blood 32 29187380
2015 Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis. Annals of the rheumatic diseases 15 25956157
2024 SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 39119875
2018 Sec16A, a key protein in COPII vesicle formation, regulates the stability and localization of the novel ubiquitin ligase RNF183. PloS one 11 29300766
1998 Monoclonal antibody P-31 recognizes a novel intermediate filament-associated protein (p250) in rat podocytes. The American journal of physiology 11 9612338
1988 Gene encoding human p250 T-cell activation antigen maps to human chromosome 11. Somatic cell and molecular genetics 3 3259339
2025 Construction of pathogenic Sec16a mutation mouse model using CRISPR/Cas9. Animal models and experimental medicine 1 41104514
2024 Targeted RNA Sequencing of Head and Neck Adenoid Cystic Carcinoma Reveals SEC16A::NOTCH1 Fusion and MET Exon 14 Skipping as Potentially Actionable Alterations. Head and neck pathology 1 39508931
2023 [Clinical value of plasma scaffold protein SEC16A in evaluating hepatitis B-related liver cirrhosis and hepatocellular carcinoma]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 0 37400387
2022 KMT2A-MLLT1 and the Novel SEC16A-KMT2A in a Cryptic 3-Way Translocation t(9;11;19) Present in an Infant With Acute Lymphoblastic Leukemia. Journal of pediatric hematology/oncology 0 34966090
2003 [Effects of selenium dioxide on regulatory regions P250 of c-fos gene]. Ai zheng = Aizheng = Chinese journal of cancer 0 12600289