Affinage

SEC16A

Protein transport protein Sec16A · UniProt O15027

Length
2357 aa
Mass
251.9 kDa
Annotated
2026-06-10
18 papers in source corpus 9 papers cited in narrative 9 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

SEC16A is a large, predominantly cytosolic scaffolding protein that organizes ER exit sites (ERES) and drives COPII-mediated ER-to-Golgi protein transport (PMID:17428803). It is recruited to ER membranes in a Sar1-dependent manner and bridges both the inner Sec23-Sec24 and outer Sec13-Sec31 COPII coat layers, such that its depletion disorganizes ERES and delays secretory transport (PMID:17428803); its stable anchoring at ERES depends on a direct interaction with LRRK2, which a Parkinson's-associated R1441C mutation disrupts independently of LRRK2 kinase activity (PMID:25201882). SEC16A coordinates secretory hand-off to the Golgi through direct binding of its unstructured N-terminal region to the head domain of the vesicle tether p115/USO1 (PMID:42169630). Beyond canonical COPII transport, SEC16A acts as a RAB10 effector that mobilizes GLUT4 from a perinuclear recycling endosome/TGN compartment to the plasma membrane upon insulin stimulation, a role independent of the full COPII coat (PMID:27354378), and during ER stress it redistributes to the cell periphery and associates with GRASP55 to support IRE1α-regulated unconventional secretion of CFTR (PMID:28067262). Through its central conserved domain it also binds and stabilizes the E3 ubiquitin ligase RNF183 against ERAD without being its substrate (PMID:29300766). Loss-of-function SEC16A variants impair COPII assembly, secretory trafficking, and provoke ER stress, with Sec16a+/- mice showing defective zymogen secretion and aggravated pancreatitis (PMID:39119875), while a central-core knock-in mutation produces neurological and memory deficits in vivo (PMID:41104514).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 High

    Established that mammalian SEC16A is the scaffold organizing ER exit sites by physically linking both COPII coat layers, answering how ERES architecture and ER export are maintained.

    Evidence Subcellular fractionation, COPII binding assays, and siRNA depletion with ER-to-Golgi transport assay in mammalian cells

    PMID:17428803

    Open questions at the time
    • Did not resolve how SEC16A is itself stably positioned at ERES
    • Structural basis of simultaneous inner/outer coat binding not defined
  2. 2014 Medium

    Identified LRRK2 as the factor anchoring SEC16A at ERES, linking a Parkinson's-associated mutation to a defect in ER export.

    Evidence Reciprocal Co-IP, confocal co-localization, siRNA knockdown with transport assay, and kinase-dead/dominant-negative mutant analysis

    PMID:25201882

    Open questions at the time
    • Direct vs. bridged nature of the LRRK2-SEC16A interaction not established
    • How R1441C disrupts binding mechanistically unresolved
  3. 2016 High

    Revealed a non-canonical SEC16A function as a RAB10 effector in insulin-stimulated GLUT4 trafficking, separating this role from full COPII coat activity.

    Evidence siRNA knockdown, insulin-dependent colocalization, GLUT4 translocation assay, and epistasis with individual COPII components in adipocytes

    PMID:27354378

    Open questions at the time
    • Why SEC23A but not other coat subunits is required is unexplained
    • Mechanism of RAB10-SEC16A coupling to vesicle biogenesis not defined
  4. 2017 Medium

    Showed SEC16A participates in both conventional and GRASP55-mediated Golgi-bypassing secretion under ER stress, placing it downstream of IRE1α signaling.

    Evidence siRNA knockdown screen, immunofluorescence relocalization, Co-IP with GRASP55, and IRE1α inhibitor/dominant-negative experiments

    PMID:28067262

    Open questions at the time
    • Signal driving SEC16A peripheral redistribution unknown
    • Direct vs. indirect SEC16A-GRASP55 association not resolved
  5. 2018 Medium

    Defined a chaperone-like role in which SEC16A's central conserved domain stabilizes E3 ligases RNF183/RNF152 against degradation rather than acting as their substrate.

    Evidence Co-IP, domain mapping, pulse-chase degradation assay, and fluorescence localization

    PMID:29300766

    Open questions at the time
    • Physiological consequence of ligase stabilization not established
    • Whether this links to ERAD regulation of ERES is unknown
  6. 2024 High

    Demonstrated in vivo that SEC16A loss-of-function impairs COPII assembly and secretion, causing ER stress and aggravating pancreatic disease.

    Evidence CRISPR loss-of-function HEK293T cells, Sec16a+/- mouse model, trafficking and ER-stress readouts, cerulein pancreatitis model

    PMID:39119875

    Open questions at the time
    • Tissue specificity of secretory vulnerability not fully mapped
    • Whether human SEC16A variants cause a defined Mendelian disorder not established
  7. 2025 Medium

    Established the central core domain as functionally critical in vivo by linking a conserved-residue mutation to learning, memory, and motor deficits.

    Evidence CRISPR/Cas9 knock-in mouse (L1551V) with novel object recognition, fear conditioning, and limb-clasping assays

    PMID:41104514

    Open questions at the time
    • Molecular mechanism connecting the mutation to neurodegeneration unresolved
    • Cellular trafficking defect underlying behavior not measured
  8. 2025 Low

    Implicated SEC16A-dependent ER exit as a regulatory node for sphingolipid homeostasis via VLC-ceramide trafficking.

    Evidence Sphingolipid metabolic flux analysis with siRNA depletion of SEC16A (preprint)

    PMID:bio_10.1101_2025.02.12.637879

    Open questions at the time
    • Preprint, single lab, no orthogonal validation
    • Whether ceramide transport is direct COPII cargo-dependent unresolved
  9. 2026 Medium

    Pinpointed a direct molecular contact between SEC16A's N-terminal motif and the p115/USO1 tether head domain that promotes efficient secretion.

    Evidence Direct binding assay, structural prediction, deletion mapping, and secretion assays with p115 binding mutants

    PMID:42169630

    Open questions at the time
    • Spatiotemporal role of this contact in vesicle tethering not defined
    • Structure of the bound complex not experimentally determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SEC16A switches between its canonical ERES-scaffolding role and its non-canonical RAB10-effector and unconventional-secretion functions remains undefined.
  • No structure of full-length SEC16A or its coat/tether complexes
  • Domain-specific regulatory mechanisms governing pathway selection unknown
  • Connection between trafficking defects and neurodegenerative phenotype unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9609507 Protein localization 1
Partners
GRASP55LRRK2RAB10SEC13SEC23ASEC24SEC31USO1
Complex memberships
COPII coat

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Mammalian SEC16A (KIAA0310p/p250) localizes to ER exit sites but is predominantly cytosolic; it is recruited to ER membranes in a Sar1-dependent manner, and interacts with both the inner COPII coat (Sec23-Sec24) and the outer coat (Sec13-Sec31). Depletion of SEC16A disorganizes ER exit sites and delays ER-to-Golgi protein transport. Subcellular fractionation, binding experiments, siRNA depletion with ER transport assay, overexpression morphology The Journal of biological chemistry High 17428803
2014 LRRK2 interacts with and co-localizes with SEC16A at ER exit sites (ERES), anchoring it there; loss of LRRK2 disperses SEC16A from ERES and impairs ER export. The LRRK2 R1441C PD mutation disrupts this interaction and ER-Golgi transport, while LRRK2 kinase activity is not required. Co-immunoprecipitation, co-localization (confocal microscopy), siRNA knockdown with ER transport assay, dominant-negative and kinase-dead mutant analysis The EMBO journal Medium 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, and SEC16A knockdown phenocopies RAB10 knockdown. SEC16A and RAB10 promote mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment. This function is independent of canonical COPII coat activity (SEC13, SEC23B, SEC31 are not required), though SEC23A is involved. siRNA knockdown, colocalization (fluorescence microscopy), GLUT4 translocation assay, epistasis with COPII components The Journal of cell biology High 27354378
2017 SEC16A is required for both conventional (COPII-mediated) and unconventional (GRASP55-mediated, Golgi-bypassing) secretion of CFTR. During unconventional secretion, SEC16A redistributes to the cell periphery and associates with GRASP55. IRE1α-mediated signaling acts as an upstream regulator of SEC16A during ER stress-associated unconventional secretion. siRNA knockdown screen, immunofluorescence localization, co-immunoprecipitation, IRE1α inhibitor/dominant-negative experiments Scientific reports Medium 28067262
2018 SEC16A interacts with the E3 ubiquitin ligase RNF183 through SEC16A's central conserved domain (CCD). SEC16A is not a substrate for RNF183, but stabilizes RNF183 against ERAD-mediated degradation and influences its localization. SEC16A similarly stabilizes the related lysosomal ligase RNF152. Co-immunoprecipitation, domain-mapping experiments, pulse-chase/degradation assay, localization by fluorescence microscopy PloS one Medium 29300766
2024 Loss-of-function SEC16A variants (including a frameshift) disrupt COPII complex formation, impede secretory vesicle trafficking from ER, and induce ER stress due to protein overload. Sec16a+/- mice show impaired zymogen secretion, exacerbated ER stress, and heightened pancreatic inflammation/fibrosis in cerulein-stimulated pancreatitis. CRISPR/Cas9-edited HEK293T cells, Sec16a+/- mouse model, vesicle trafficking assay, ER stress markers, cerulein pancreatitis model Advanced science High 39119875
2026 The head domain of the Golgi vesicle tether p115 (USO1) binds directly to a conserved motif in the unstructured N-terminal region of SEC16A. Mutations in p115 that block this interaction reduce the efficiency of secretion. Direct binding assay, structural prediction, deletion mapping, secretion efficiency assay with p115 binding mutants Journal of cell science Medium 42169630
2025 SEC16A, as a component of the COPII network, is required for VLC-ceramide trafficking from the ER to the Golgi apparatus. Depletion of SEC16A abolished VLC-sphingomyelin synthesis triggered by cholesterol depletion, demonstrating that SEC16A-dependent COPII-mediated ER exit is a regulatory node for sphingolipid homeostasis. Sphingolipid metabolic flux analysis, siRNA depletion of SEC16A, sphingolipid trafficking assay bioRxivpreprint Low bio_10.1101_2025.02.12.637879
2025 A knock-in mouse model carrying the Sec16a L1551V mutation (equivalent to human L1536V in the conserved central core region of SEC16A) shows neurological impairment including deficits in learning, memory, and limb-clasping behavior consistent with neurodegenerative disease, establishing that the central core domain is functionally important in vivo. CRISPR/Cas9 knock-in mouse model, novel object recognition test, cued fear conditioning, limb-clasping behavioral assay Animal models and experimental medicine Medium 41104514

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 49 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
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 3 39508931
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
2026 The Golgi vesicle tether p115/USO1 can bind directly to the ER exit site organiser Sec16A. Journal of cell science 0 42169630
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

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