Affinage

SEC23A

Protein transport protein Sec23A · UniProt Q15436

Length
765 aa
Mass
86.2 kDa
Annotated
2026-06-10
33 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEC23A is an essential inner-coat component of COPII-coated vesicles that mediates anterograde ER-to-Golgi transport of secretory cargo, with a preferential role in trafficking large extracellular-matrix proteins such as collagens (PMID:16980979, PMID:26494538). Loss of SEC23A function—through the disease-causing F382L substitution in human cranio-lenticulo-sutural dysplasia or nonsense mutation in zebrafish—abolishes cell-free vesicle budding, mislocalizes the outer-coat protein SEC31, distends the ER, and blocks secretion of type II collagen and other ECM proteins into cartilage matrix (PMID:16980979, PMID:16980978). In mice, SEC23A deficiency causes mid-embryonic lethality with intracellular collagen accumulation and unfolded protein response activation while sparing fibronectin secretion, establishing cargo selectivity (PMID:26494538); SEC23A and its paralog SEC23B share an indistinguishable interactome and are biochemically interchangeable, so distinct human diseases reflect tissue-specific expression rather than functional divergence (PMID:30065114, PMID:34818036). SEC23A transcription is driven by the ER-stress transcription factor BBF2H7/CREB3L2, which binds the SEC23A promoter to support collagen trafficking and chondrocyte and hepatic stellate cell differentiation (PMID:19767744, PMID:28801610, PMID:22495181), and by pY705-STAT3 (PMID:37670384). Its trafficking activity is post-translationally regulated: ULK1 phosphorylates SEC23A at S207/S312/T405, reducing SEC23A–SEC31A interaction, aggregating ER exit sites, and inhibiting cargo transport during autophagy (PMID:28486929), while non-canonical mono-ubiquitylation at cysteines C432/C449 modulates ER-membrane association without driving degradation (PMID:28553408). Through control of the tumor-cell secretome—exporting metastasis-suppressive proteins including Igfbp4, Tinagl1, S100A8 and PF4—SEC23A suppresses metastatic colonization and is silenced by multiple miRNAs (miR-200, miR-375, miR-1227) that target its 3'-UTR (PMID:21822286, PMID:21593139, PMID:32811814, PMID:34421345, PMID:34831007). SEC23A further links ER homeostasis to cancer cell survival and stem-cell self-renewal by promoting FAM134B-mediated ER-phagy and ANXA2-dependent autophagy (PMID:35236368, PMID:37670384).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 High

    Established that SEC23A is a functionally essential COPII coat component whose loss disrupts ER-to-Golgi vesicle budding and ECM secretion, explaining a human Mendelian skeletal disorder.

    Evidence Positional cloning of a disease mutation, cell-free vesicle budding assay with mutant protein, EM/immunofluorescence in patient fibroblasts and zebrafish mutants

    PMID:16980978 PMID:16980979

    Open questions at the time
    • Did not define the full cargo spectrum
    • Mechanism of SEC31 mislocalization not resolved at structural level
  2. 2009 High

    Identified the transcriptional control of SEC23A by placing it downstream of the ER-stress transcription factor BBF2H7/CREB3L2, linking the UPR to secretory capacity.

    Evidence Bbf2h7 knockout mice, promoter ChIP/luciferase, Sec23a rescue of knockout chondrocytes

    PMID:19767744

    Open questions at the time
    • Did not address whether other ER-stress factors converge on the same promoter
    • Tissue scope beyond chondrocytes unaddressed
  3. 2011 High

    Revealed a non-cell-autonomous role: SEC23A controls the secretome to suppress metastasis, and is silenced by miRNAs in cancer.

    Evidence 3'-UTR reporter assays, secretome proteomics, mouse metastasis and prostate cancer growth models

    PMID:21593139 PMID:21822286

    Open questions at the time
    • Whether secretory defect or specific cargo loss drives the phenotype not fully separated
    • miR-375 study is single-lab Medium confidence
  4. 2015 High

    Demonstrated cargo selectivity in vivo—SEC23A is preferentially required for collagen export but dispensable for fibronectin—and that paralogs handle overlapping but distinct cargo.

    Evidence Sec23a knockout mice with secreted vs. intracellular cargo analysis and UPR markers; Sec23a/Sec23b compound null analysis

    PMID:26494538

    Open questions at the time
    • Molecular basis for collagen-over-fibronectin preference unresolved
    • Cargo adaptor requirements not defined
  5. 2017 High

    Uncovered post-translational regulation of SEC23A trafficking activity by ULK1 phosphorylation and by non-canonical cysteine mono-ubiquitylation, coupling COPII output to autophagy and ER-membrane association.

    Evidence In vitro kinase assays, phosphosite mutagenesis, SEC23A-SEC31A Co-IP, ERES imaging; MS Gly-Gly mapping and cysteine mutagenesis

    PMID:28486929 PMID:28553408

    Open questions at the time
    • Ubiquitin ligase/deubiquitinase for C432/C449 not identified
    • In vivo physiological context of these modifications untested
    • Ubiquitylation study is single-lab Medium confidence
  6. 2018 High

    Proved biochemical equivalence of SEC23A and SEC23B, redefining their distinct disease phenotypes as a consequence of differential expression rather than functional divergence.

    Evidence Interactome MS, yeast complementation, zebrafish rescue, mouse knock-in of Sec23a coding sequence into the Sec23b locus

    PMID:30065114

    Open questions at the time
    • Determinants of tissue-specific expression not mapped
    • Does not exclude subtle paralog-specific kinetics
  7. 2021 High

    Extended paralog interchangeability to human cells and identified specific secreted anti-metastatic cargoes (S100A8, PF4) and their downstream pathways.

    Evidence CRISPR SEC23B-deficient HUDEP-2 rescue; secretome analysis with autophagy (S100A8-BECLIN1) and MAPK/ERK (PF4-SPARC) readouts in melanoma lines

    PMID:32811814 PMID:34421345 PMID:34818036

    Open questions at the time
    • Cargo-specific recognition mechanisms not defined
    • Cancer cargo studies are single-lab Medium confidence
  8. 2023 Medium

    Connected SEC23A to ER-stress survival circuits, showing it both responds to pY705-STAT3 transcriptionally and drives ER-phagy (FAM134B) and autophagy (ANXA2) to govern stem-cell self-renewal and apoptosis resistance.

    Evidence ChIP/luciferase for STAT3, Co-IP/MS for SEC23A-ANXA2, autophagy markers, TEM, xenografts in melanoma and gastric cancer

    PMID:35236368 PMID:37670384

    Open questions at the time
    • Direct vs. indirect link between COPII trafficking and ER-phagy unclear
    • Single-lab studies without independent replication
    • Mechanism of ANXA2 relocalization not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SEC23A achieves cargo selectivity (e.g., preferential collagen export), and the structural basis by which disease variants disrupt the SEC23-SAR1 coat interface, remain unresolved.
  • E599K dominant-negative mechanism rests only on structural modeling without binding assay [#15]
  • No high-resolution structure of human SEC23A-SAR1 in the corpus
  • Cargo adaptor logic for large vs. small cargoes undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9609507 Protein localization 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ANXA2SAR1SEC31A
Complex memberships
COPII coat

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SEC23A is an essential component of COPII-coated vesicles mediating ER-to-Golgi transport; the disease-causing F382L substitution results in loss of SEC23A function in cell-free vesicle budding assays, causing gross ER dilatation and cytoplasmic mislocalization of SEC31 in patient fibroblasts. Positional cloning, cell-free vesicle budding assay, electron microscopy, immunofluorescence, zebrafish morpholino knockdown Nature genetics High 16980979
2006 Zebrafish sec23a loss-of-function (crusher nonsense mutation L402X) causes chondrocyte ER distension and failure to secrete type II collagen and other ECM proteins into cartilage extracellular matrix, establishing SEC23A as an integral COPII component required for ECM secretion in chondrocytes. Positional cloning, zebrafish genetic mutant analysis, immunofluorescence, electron microscopy; sec23b knockdown (morpholino) shows paralog is also required Nature genetics High 16980978
2009 BBF2H7 (CREB3L2) directly binds a CRE-like sequence in the Sec23a promoter to activate its transcription in response to ER stress; introduction of Sec23a into Bbf2h7-/- chondrocytes fully restores impaired cartilage matrix protein transport and secretion, placing SEC23A downstream of BBF2H7 in ER stress-to-ER-Golgi trafficking signaling. Bbf2h7 knockout mouse generation, promoter binding assay (ChIP/luciferase), Sec23a rescue experiment in knockout chondrocytes, immunofluorescence, genetic epistasis Nature cell biology High 19767744
2011 miR-200s directly target the 3'-UTR of SEC23A mRNA to suppress its expression, reducing secretion of metastasis-suppressive proteins Igfbp4 and Tinagl1 from the tumor cell secretome, thereby promoting metastatic colonization. 3'-UTR reporter assay, proteomic/genomic analysis of secretome, functional rescue experiments in mouse breast cancer metastasis models Nature medicine High 21822286
2011 miR-375 and miR-200c each target the 3'-UTR of SEC23A mRNA to downregulate SEC23A protein expression; ectopic overexpression of SEC23A in prostate cancer cell lines reduces cell growth without inducing apoptosis, while inhibition of SEC23A stimulates proliferation. 3'-UTR luciferase reporter assay, Western blot, qRT-PCR, cell growth assays in LNCaP and DU145 cells Molecular cancer research : MCR Medium 21593139
2013 ER stress impairs membrane association of COPII components, particularly Sec23a, reducing COPII vesicle formation at ER exit sites, and alters Sec23a cycling at ERESs. Fluorescence microscopy (ERES imaging), COPII vesicle formation assay, ER stress induction with pharmacological agents FEBS letters Medium 23994533
2015 SEC23A-deficient mice exhibit mid-embryonic lethality with defective extraembryonic membrane development and neural tube opening; multiple collagen types accumulate intracellularly in SEC23A-deficient connective tissue cells, triggering unfolded protein response, while fibronectin secretion is unaffected, showing SEC23A preferentially transports collagen cargo. SEC23A and SEC23B transport overlapping but distinct cargo spectra in vivo. Sec23a knockout mouse, immunofluorescence, Western blot for secreted vs. intracellular collagen/fibronectin, UPR markers; Sec23a/Sec23b compound null analysis Scientific reports High 26494538
2017 ULK1 phosphorylates SEC23A at serine 207, serine 312, and threonine 405; phosphorylation at S207 reduces the interaction between SEC23A and SEC31A, causes ERES aggregation, and inhibits ER-to-Golgi cargo transport during autophagy induction. In vitro kinase assay, site-directed mutagenesis (S207A/D, S312A/D, T405A/E), Co-immunoprecipitation (SEC23A–SEC31A interaction), live-cell imaging of ERES, cargo transport assays under amino acid starvation/rapamycin/ULK1 overexpression BMC cell biology High 28486929
2017 Sec23a ubiquitylation occurs at non-canonical cysteine residues (C432 and C449) as mono-ubiquitin attachment; mutation of these sites affects Sec23a interaction with ER membrane and modulates COPII formation, without targeting Sec23a for degradation. Co-immunoprecipitation, mass spectrometry (Gly-Gly remnant identification), site-directed mutagenesis of C432 and C449, immunofluorescence The open biochemistry journal Medium 28553408
2017 CREB3L2/BBF2H7 transcriptionally upregulates SEC23A (and SEC24D) expression during hepatic stellate cell (HSC) activation; knockdown of SEC23A abrogates HSC activation, establishing that SEC23A-mediated ER-to-Golgi trafficking is required for this differentiation process. siRNA knockdown, Western blot, RT-PCR, HSC activation assays Scientific reports Medium 28801610
2018 SEC23A and SEC23B have indistinguishable intracellular protein interactomes; both complement yeast Sec23; a Sec23a coding sequence knocked into the Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype in mice, demonstrating equivalent biochemical function with tissue-specific expression differences accounting for distinct phenotypes. Mass spectrometry interactome, yeast complementation, zebrafish transgene rescue, mouse knock-in (Sec23a coding sequence into Sec23b locus) Proceedings of the National Academy of Sciences of the United States of America High 30065114
2018 Sec23a functions downstream of miR-200c to suppress oligometastatic-to-polymetastatic progression via its secretome; mass spectrometric analysis of secretory protein profiles shows Sec23a-dependent secretome modifies the tumor microenvironment. miR-200c overexpression/Sec23a knockdown in paired oligometastatic/polymetastatic melanoma lines, in vivo metastasis assays, mass spectrometry of secretome EBioMedicine Medium 30301603
2020 S100A8 is transported by SEC23A (as COPII cargo) and inhibits metastatic colonization via autocrine activation of autophagy through a SEC23A–S100A8–BECLIN1–autophagy axis. SEC23A knockdown/overexpression, secretome analysis, autophagy assays (LC3, BECLIN1), paired oligometastatic/polymetastatic melanoma cell lines, in vivo colonization assays Cell death & disease Medium 32811814
2021 SEC23A transports PF4 as COPII cargo; secreted PF4, cooperating with SPARC, inhibits melanoma metastasis through inhibition of the MAPK/ERK signaling pathway. SEC23A overexpression/knockdown in paired melanoma lines, secretome analysis, MAPK/ERK phosphorylation assays, in vivo metastasis assays International journal of biological sciences Medium 34421345
2021 SEC23A expression is rescued in SEC23B-deficient HUDEP-2 human erythroid cells and reverses CDAII-like features upon differentiation, demonstrating functional interchangeability of the paralogs in human erythroid cells. CRISPR-generated SEC23B-deficient HUDEP-2 cells, SEC23A overexpression rescue, erythroid differentiation assays Science advances High 34818036
2021 A monoallelic SEC23A E599K variant disrupts a residue predicted by 3D structural modeling to be involved in direct binding between SEC23 and SAR1 subunits of the COPII coat, suggesting dominant-negative disruption of the SEC23 multimer as the pathomechanism. Trio genome sequencing, familial segregation, 3D structural modeling of SEC23–SAR1 interface American journal of medical genetics. Part A Low 34580982
2021 miR-1227 directly targets SEC23A (validated by luciferase assay); inhibition of SEC23A is sufficient to shift extracellular vesicle shedding toward large EVs (large oncosomes) and away from small EVs (exosomes). Luciferase 3'-UTR assay, qPCR, Western blot, SEC23A siRNA knockdown, EV size/population analysis Cancers Medium 34831007
2022 SEC23A inhibits self-renewal of melanoma cancer stem cells by promoting ER stress and thereby inducing FAM134B-mediated ER-phagy; inhibition of SEC23A reduces ER stress and consequently suppresses FAM134B-induced ER-phagy, increasing stemness. Stable CSC cell lines from M14 and A375 melanoma, SEC23A knockdown/overexpression, LC3/P62 autophagy markers, transmission electron microscopy of ER morphology, spheroid formation and single-cell cloning assays, subcutaneous xenograft Cell communication and signaling : CCS Medium 35236368
2023 SEC23A is transcriptionally upregulated by ER stress-induced pY705-STAT3; elevated SEC23A promotes autophagy by regulating cellular localization of ANXA2, and the SEC23A–ANXA2–autophagy axis protects gastric cancer cells from ER stress-induced apoptosis, creating a negative feedback loop. ChIP assay and luciferase reporter (STAT3 binding to SEC23A promoter), Co-immunoprecipitation and mass spectrometry (SEC23A–ANXA2 interaction), subcellular localization experiments, autophagy assays, in vitro and in vivo functional experiments Journal of experimental & clinical cancer research : CR Medium 37670384
2012 The BBF2H7-mediated SEC23A pathway is required for ER-to-Golgi procollagen (COL1 and COL3) trafficking in dermal fibroblasts; BBF2H7 knockdown reduces collagen expression and causes Golgi dysmorphology due to COPII hypoplasia, phenotypes rescued by the pathway. siRNA knockdown of BBF2H7, immunofluorescence microscopy of Golgi and COPII, RT-PCR/Western blot for collagen expression, IGF-I stimulation assays The Journal of investigative dermatology Medium 22495181
2012 TFII-I transcription factors (GTF2I/GTF2IRD1) are recruited to the promoter of SEC23A in human neural crest progenitor cells, identifying SEC23A as a direct TFII-I target gene. ChIP-chip (chromatin immunoprecipitation with tiling promoter arrays) in human neural crest progenitor cells The Cleft palate-craniofacial journal Low 23145914
2026 Salidroside directly binds SEC23A (identified by DARTS assay and molecular docking); stress factors (Substance P/cortisol) specifically upregulate SEC23A, which salidroside suppresses; SEC23A knockdown potentiates salidroside's anti-melanogenic effects in the stress model via dual activation of the SEC23A–p-ERK–MITF axis and inhibition of NK1R–p38–MITF axis. DARTS (Drug Affinity Responsive Target Stability) assay, molecular docking, SEC23A siRNA knockdown, Western blot for p-ERK/MITF/p38, melanin content and tyrosinase activity assays, in vivo zebrafish and mouse models Pharmaceuticals (Basel, Switzerland) Medium 41901332

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nature medicine 532 21822286
2006 Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nature genetics 257 16980979
2009 Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis. Nature cell biology 192 19767744
2006 Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation. Nature genetics 163 16980978
2016 miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. Molecular cancer 117 27832783
2011 Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma. Molecular cancer research : MCR 94 21593139
2018 Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo. Proceedings of the National Academy of Sciences of the United States of America 65 30065114
2016 MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression. BMC cancer 63 27495250
2017 ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic. BMC cell biology 45 28486929
2016 MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib. Oncotarget 45 27036030
2015 Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. Scientific reports 43 26494538
2018 Sec23a mediates miR-200c augmented oligometastatic to polymetastatic progression. EBioMedicine 26 30301603
2013 Endoplasmic reticulum stress reduces COPII vesicle formation and modifies Sec23a cycling at ERESs. FEBS letters 26 23994533
2017 CREB3L2-mediated expression of Sec23A/Sec24D is involved in hepatic stellate cell activation through ER-Golgi transport. Scientific reports 24 28801610
2023 SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop. Journal of experimental & clinical cancer research : CR 21 37670384
2016 Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A. Cold Spring Harbor molecular case studies 19 27148587
2020 S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy. Cell death & disease 18 32811814
2021 SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II. Science advances 15 34818036
2021 SEC23A Inhibit Melanoma Metastatic through Secretory PF4 Cooperation with SPARC to Inhibit MAPK Signaling Pathway. International journal of biological sciences 14 34421345
2012 BBF2H7-mediated Sec23A pathway is required for endoplasmic reticulum-to-Golgi trafficking in dermal fibroblasts to promote collagen synthesis. The Journal of investigative dermatology 14 22495181
2017 Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER. The open biochemistry journal 13 28553408
2012 ChIP-Chip Identifies SEC23A, CFDP1, and NSD1 as TFII-I Target Genes in Human Neural Crest Progenitor Cells. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 13 23145914
2021 The Metarhizium anisopliae Toxin, Destruxin A, Interacts with the SEC23A and TEME214 Proteins of Bombyx mori. Journal of fungi (Basel, Switzerland) 12 34201102
2022 Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy. Cell communication and signaling : CCS 11 35236368
2021 miR-1227 Targets SEC23A to Regulate the Shedding of Large Extracellular Vesicles. Cancers 6 34831007
2022 MiR-29b-3p Inhibits the Inflammation Injury in Human Umbilical Vein Endothelial Cells by Regulating SEC23A. Biochemical genetics 4 35190931
2021 A monoallelic SEC23A variant E599K associated with cranio-lenticulo-sutural dysplasia. American journal of medical genetics. Part A 4 34580982
2025 The impact of SEC23A on 5-FU chemotherapy sensitivity and its involvement in endoplasmic reticulum stress-induced apoptosis in colorectal cancer. Apoptosis : an international journal on programmed cell death 2 39904858
2025 Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression. Acta biochimica et biophysica Sinica 2 40400443
2023 Differential methylation in CD44 and SEC23A is associated with time preference in older individuals. Economics and human biology 2 36812724
2023 Novel compound heterozygous variants of the SEC23A gene in a Chinese family with cranio-lenticulo-sutural dysplasia based on data from a large cohort of congenital cataract patients. BMC medical genomics 1 37828500
2026 Salidroside Selectively Binds to SEC23A and Ameliorates Psychological Stress-Induced Hyperpigmentation. Pharmaceuticals (Basel, Switzerland) 0 41901332
2024 First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review. Genes 0 38275611

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