Affinage

EXOC3

Exocyst complex component 3 · UniProt O60645

Length
745 aa
Mass
85.6 kDa
Annotated
2026-04-28
41 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXOC3 (Sec6) is a core subunit of the octameric exocyst tethering complex that directs the docking and fusion of secretory vesicles at polarized membrane domains, functioning at the plasma membrane and trans-Golgi network in processes ranging from basolateral cargo delivery in epithelia to granule secretion in platelets (PMID:1523887, PMID:9630218, PMID:11696560, PMID:33560379). Sec6 directly binds SNARE complexes and the SM protein Sec1/Munc18 in a mutually exclusive manner: upon vesicle arrival, Sec6 releases the t-SNARE Sec9 and recruits Sec1, thereby promoting rather than inhibiting SNARE-mediated membrane fusion (PMID:22114349, PMID:26446795). The exocyst complex containing EXOC3 is recruited to sites of cell-cell contact through interactions with E-cadherin and nectin and operates downstream of Rab11 and Ral GTPases to route vesicles from recycling endosomes to the cell surface (PMID:14709721, PMID:15897260, PMID:16224820). EXOC3 knockdown also modulates p38 MAPK/HSP27 and NF-κB signaling cascades, and conditional knockout in mouse platelets disrupts GPVI-dependent granule secretion while paradoxically accelerating arterial thrombosis (PMID:29729335, PMID:26247921, PMID:33560379).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    Establishing that SEC6 encodes an essential soluble protein required for post-Golgi vesicle fusion with the plasma membrane defined its fundamental role in the secretory pathway.

    Evidence Yeast gene cloning by complementation, gene disruption lethality, subcellular fractionation

    PMID:1523887

    Open questions at the time
    • No interacting partners identified
    • No structural information
    • Mammalian ortholog not yet characterized
  2. 1995 High

    Identifying Sec6 as a stable subunit of the multisubunit Sec6/8 complex that localizes to polarized bud tips placed it within a defined molecular machine for polarized exocytosis.

    Evidence Immobilized metal affinity chromatography, gel filtration, co-IP, and immunofluorescence in S. cerevisiae

    PMID:7615633

    Open questions at the time
    • Stoichiometry and complete subunit composition of the complex not yet defined
    • Function of individual subunits within the complex unknown
  3. 1998 High

    Demonstrating that the Sec6/8 complex is recruited to cell-cell contacts upon calcium-dependent adhesion and specifically directs basolateral (not apical) membrane delivery in epithelial cells established the complex's role in polarized trafficking in mammalian cells.

    Evidence Function-blocking antibodies in streptolysin-O-permeabilized MDCK cells with domain-specific cargo readouts; co-IP with septin filaments in neurons

    PMID:9630218 PMID:9655500

    Open questions at the time
    • Which subunit(s) mediate membrane-domain specificity remains unclear
    • Mechanism of recruitment to cell-cell contacts unresolved
  4. 2001 High

    Showing that the exocyst functions at both the TGN and the plasma membrane, with antibodies against each pool blocking distinct transport steps, revealed that the complex acts at multiple stations along the exocytic route.

    Evidence Antibody inhibition in semiintact cells with VSVG cargo tracking, Brefeldin A experiments

    PMID:11696560

    Open questions at the time
    • How the complex transitions between TGN and PM pools is unknown
    • Specific contribution of Sec6 versus other subunits at each station not resolved
  5. 2004 High

    Identifying E-cadherin and nectin-2α as upstream recruiters of the exocyst to the apical junctional complex explained how adhesion controls vesicle delivery to cell-cell contacts.

    Evidence Co-IP with surface-labeled adhesion proteins; reconstitution of exocyst recruitment in fibroblasts co-expressing E-cadherin and nectin

    PMID:14709721

    Open questions at the time
    • Direct binding subunit(s) within the exocyst that contact E-cadherin/nectin not mapped
    • Regulation of the interaction not defined
  6. 2005 High

    Structural and genetic studies established that Ral GTPases regulate the exocyst through mutually exclusive binding to Sec5 and Exo84, and that the Rab11-exocyst axis routes vesicles from recycling endosomes to the plasma membrane in epithelia.

    Evidence Crystal structures of RalA–Sec5 and RalA–Exo84 complexes; Drosophila sec6 loss-of-function showing vesicle accumulation and DE-Cadherin trapping in Rab11-positive endosomes; co-IP of Rab11–Sec15 and Armadillo–Sec10

    PMID:12839989 PMID:15897260 PMID:15920473 PMID:16224820

    Open questions at the time
    • Whether Sec6 itself directly contacts Ral or Rab11 is unknown
    • How Ral and Rab11 signals are integrated at the level of the holo-complex remains unresolved
  7. 2011 High

    Revealing that Sec6 directly binds the SM protein Sec1 in a manner mutually exclusive with SNARE binding defined a hand-off mechanism coordinating vesicle tethering with SNARE-mediated fusion.

    Evidence In vitro pull-down and binding competition assays in yeast

    PMID:22114349

    Open questions at the time
    • Temporal sequence of hand-off not demonstrated in vivo
    • Structural basis of mutual exclusivity not determined
  8. 2015 High

    Showing that Sec6 binds assembled SNARE complexes without inhibiting their assembly—and that disrupting this interaction impairs growth—revised the model from inhibitory gatekeeper to a positive regulator of SNARE complex formation.

    Evidence In vitro SNARE assembly kinetics, cross-linking mass spectrometry mapping the Sec6–SNARE interface, yeast mutagenesis growth assays

    PMID:26446795

    Open questions at the time
    • Whether Sec6 stabilizes or activates SNARE complexes post-assembly is unclear
    • Interface residues not confirmed by structural methods
  9. 2016 Medium

    EXOC3 knockdown studies linked the exocyst subunit to NF-κB and p38 MAPK signaling cascades, suggesting broader roles beyond vesicle trafficking in cytokine-stimulated signaling.

    Evidence siRNA knockdown in HeLa cells with IκBα degradation, p65 translocation, and phospho-p38/HSP27 readouts

    PMID:26247921 PMID:29729335

    Open questions at the time
    • No direct biochemical mechanism connecting Sec6 to kinase activation
    • Single-lab observations not independently replicated
    • Possible indirect effects via impaired trafficking of signaling receptors not excluded
  10. 2021 High

    Conditional EXOC3 knockout in platelets demonstrated its requirement for GPVI-dependent granule secretion and integrin activation, yet paradoxically accelerated thrombosis through enhanced PAR4-mediated ADP release, revealing receptor-specific roles in vivo.

    Evidence Conditional knockout mice (Cre-lox), platelet aggregation, flow cytometry, ferric chloride arterial thrombosis model

    PMID:33560379

    Open questions at the time
    • Mechanism of paradoxical PAR4-pathway enhancement in the absence of EXOC3 is unexplained
    • Whether phenotype reflects Sec6-specific function or general exocyst disruption is unknown
  11. 2024 Medium

    Male germline-specific knockout showed EXOC3 is dispensable for spermatogenesis, distinguishing it from other exocyst subunits (SEC3, EXO70) and revealing functional non-equivalence among subunits in this tissue.

    Evidence Conditional knockout in mouse male germline with histological analysis

    PMID:38325858

    Open questions at the time
    • Whether other exocyst subunits compensate in the germline is untested
    • Subtle fertility or sperm function defects not assessed beyond histology

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of human EXOC3 and atomic-detail understanding of how Sec6 coordinates the SNARE/SM hand-off in the context of the assembled holo-exocyst complex remain unresolved.
  • No high-resolution structure of full-length human EXOC3
  • No cryo-EM or crystal structure of Sec6 within the assembled mammalian exocyst
  • Structural basis of Sec6–SNARE and Sec6–Sec1 mutual exclusivity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-9609507 Protein localization 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2 R-HSA-109582 Hemostasis 1
Complex memberships
exocyst complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Sec6 (EXOC3 ortholog in yeast) is a stable component of the Sec6/8/15 multisubunit complex (~1-2 MDa) that localizes to small bud tips in S. cerevisiae, identifying its position in the exocytic machinery at sites of polarized secretion. Immobilized metal affinity chromatography, gel filtration, sucrose velocity centrifugation, coimmunoprecipitation, immunofluorescence The Journal of cell biology High 7615633
1992 SEC6 encodes an 85 kDa soluble protein required for fusion of post-Golgi vesicles with the plasma membrane in yeast; SEC6 is essential for growth and its product sediments at 14S in the soluble fraction. Gene cloning by complementation, nucleotide sequencing, gene disruption, subcellular fractionation Yeast (Chichester, England) High 1523887
1998 In MDCK epithelial cells, the Sec6/8 (exocyst) complex is cytosolic in non-polarized cells and is rapidly recruited (~70%) to sites of cell-cell contact upon calcium-dependent adhesion; Sec8 antibodies in permeabilized cells inhibit LDL receptor delivery to the basolateral membrane but not apical delivery of p75NTR, demonstrating that the complex specifically directs vesicle delivery to the basolateral membrane. Immunofluorescence, streptolysin-O permeabilization assay with function-blocking antibodies, subcellular fractionation Cell High 9630218
1998 The rat brain Sec6/8 complex coimmunoprecipitates with septin filaments (including CDC10) and adopts a 'T' or 'Y' shaped conformation by electron microscopy, establishing a physical interaction between the exocyst and septin complexes at the plasma membrane of neurons. Coimmunoprecipitation, electron microscopy of purified complexes Neuron High 9655500
2001 The Sec6/8 complex localizes to both the trans-Golgi network (TGN) and plasma membrane in mammalian cells and is required for multiple steps of exocytic transport; antibodies against TGN-bound or plasma membrane-bound Sec6/8 each cause cargo accumulation at distinct intracellular sites, and Brefeldin A treatment blocks plasma membrane recruitment while blocking exocytosis causes TGN accumulation. Immunofluorescence colocalization with VSVG-tsO45 cargo, Brefeldin A treatment, antibody inhibition in semiintact cells The Journal of cell biology High 11696560
2001 Human Sec3 (hSec3), the last mammalian exocyst subunit to be identified, interacts with Sec5 and Sec8 in yeast two-hybrid assays but lacks the Rho1-binding site present in yeast Sec3p; GFP-Exo70 (but not other subunits) localizes to lateral membrane cell-cell contacts in MDCK cells and its overexpression disrupts tight monolayer formation. Sequence cloning, yeast two-hybrid, GFP-fusion imaging in MDCK cells Proceedings of the National Academy of Sciences of the United States of America Medium 11493706
2004 The Sec6/8 complex is recruited to the apical junctional complex in epithelial cells via direct interaction with E-cadherin and nectin-2α; co-expression of both adhesion proteins in fibroblasts is sufficient to recruit the complex to cell-cell contacts, placing E-cadherin/nectin complexes upstream of exocyst localization. Coimmunoprecipitation with surface-labeled E-cadherin and nectin-2α, high-molecular-mass fractionation, fibroblast reconstitution Journal of cell science High 14709721
2000 In pancreatic acinar and brain cells, Sec8 coimmunoprecipitates Sec6, IP3R3, Gβγ, plasma membrane Ca2+ pump, Gαq, PLCβ1, and IP3R1; interaction between Sec6/8 and Ca2+ signaling proteins is mediated by actin filaments; anti-Sec6/Sec8 antibodies inhibit Ca2+ signaling upstream of Ca2+ release, and actin disruption causes Sec6/8 translocation to cytosol and impairs polarized Ca2+ waves. Immunoprecipitation, confocal immunolocalization, actin depolymerization (latrunculin B), antibody inhibition experiments The Journal of cell biology High 10973998
2003 Crystal structure of the Sec5 Ral-binding domain (immunoglobulin-like β-sandwich) in complex with RalA-GppNHp at 2.1 Å reveals a nucleotide-dependent switch mechanism; key residues Sec5 Thr11, Arg27, and RalA Glu38 are required for complex formation, establishing the structural basis of GTP-dependent exocyst regulation by Ral GTPases. X-ray crystallography, isothermal titration calorimetry, mutagenesis The EMBO journal High 12839989
2005 Crystal structure of the Exo84 Ral-binding domain (pleckstrin homology fold) in complex with active RalA shows that Exo84 and Sec5 competitively and mutually exclusively bind RalA via overlapping switch-region interfaces; key residues determining specificity were confirmed by mutagenesis. X-ray crystallography, mutagenesis, biochemical binding assays The EMBO journal High 15920473
2005 In Drosophila epithelial cells, loss of sec6 (but not sec5 or sec8) causes accumulation at adherens junctions; in photoreceptors, reduced Sec6 leads to accumulation of secretory vesicles and failure to transport proteins to the apical rhabdomere; Rab11 forms a complex with Sec5, and Sec5 interacts with Sec6, positioning the exocyst as a Rab11 effector for apical membrane protein transport. Drosophila genetics (loss-of-function mutations), immunolocalization, coimmunoprecipitation (Rab11-Sec5-Sec6) The Journal of cell biology High 15897260
2005 In Drosophila epithelial cells, sec5, sec6, and sec15 loss-of-function results in accumulation of DE-Cadherin in an enlarged Rab11-positive recycling endosomal compartment and blocks DE-Cad delivery to the plasma membrane; Rab11 interacts with Sec15 and Armadillo interacts with Sec10, placing the exocyst in a Rab11-dependent recycling endosome-to-membrane trafficking pathway. Drosophila genetics, immunofluorescence, coimmunoprecipitation Developmental cell High 16224820
2011 Yeast Sec6 directly binds the SM protein Sec1 (Munc18 family); the Sec6-Sec1 interaction is mutually exclusive with Sec6-Sec9 (SNARE) interaction but compatible with Sec6-exocyst assembly; the Sec6-exocyst interaction is incompatible with Sec6-Sec9 binding. Upon vesicle arrival, Sec6 is proposed to release Sec9 and recruit Sec1 for coordinated SNARE complex formation. In vitro binding assays, pull-down, yeast genetics Molecular biology of the cell High 22114349
2015 Yeast Sec6 directly binds assembled binary (Sec9-Sso1) and ternary (Sec9-Sso1-Snc2) SNARE complexes but does not inhibit SNARE assembly rate; cross-linking/mass spectrometry identified Sec6 residues at the interface, and mutation of these residues causes a growth defect, suggesting Sec6 promotes rather than inhibits SNARE complex assembly. In vitro SNARE assembly assays, cross-linking mass spectrometry, yeast mutagenesis growth assays The Journal of biological chemistry High 26446795
2003 In neurons, Sec6 concentrates at the inside of the presynaptic plasma membrane (distinct from cytoplasmic Sec8); Sec6 is transported along neurites on secretogranin II-positive vesicles, identifying it as a cargo associated with dense-core vesicle transport to presynaptic sites. Immunolocalization (confocal), subcellular fractionation, live transport imaging in neurons and PC12 cells Neuroscience Medium 12763070
2018 EXOC3 (Sec6) knockdown in mammalian cells suppresses phosphorylation of p38 MAPK (via MKK3/6), MK2, and HSP27 at Ser78/Ser82, reduces cell migration, and promotes apoptosis after TNF-α/cycloheximide treatment, placing Sec6 upstream of the MKK3/6-p38-MK2-HSP27 signaling axis. siRNA knockdown, Western blotting for phospho-proteins, cell migration assay, apoptosis assay Cellular signalling Medium 29729335
2016 EXOC3 (Sec6) knockdown in HeLa cells inhibits IκBα degradation and delays p65 nuclear translocation after TNF-α stimulation; Sec6 regulates NF-κB activity via control of ERK and p90RSK1 phosphorylation and IκBα phosphorylation at Ser32. siRNA knockdown, Western blotting, nuclear translocation assay, luciferase reporter assay Journal of cellular physiology Medium 26247921
2014 EXOC3 (Sec6) regulates cytoplasmic translocation and degradation of p27 by promoting p27 phosphorylation at Thr157 and through interactions with Jab1 (CSN5) and Siah1, thereby suppressing cell cycle progression. siRNA knockdown, coimmunoprecipitation, Western blotting, cell cycle analysis Cellular signalling Low 24949832
2021 Conditional knockout of EXOC3 in mouse megakaryocytes/platelets causes defects in platelet aggregation, integrin activation, α-granule/dense granule/lysosomal granule secretion after GPVI stimulation, and reduces surface GPVI levels; paradoxically, PAR4 activation increases dense granule secretion and integrin activation in KO platelets via enhanced ADP release; arterial thrombosis is accelerated in KO mice. Conditional knockout (Cre-lox), platelet aggregation assay, flow cytometry, phosphorylation assays, tail bleeding time, ferric chloride arterial thrombosis model Blood advances High 33560379
2020 Tnfaip2 (mouse EXOC3 ortholog) acts epistatically upstream of vimentin (Vim) to control triacylglycerol synthesis and lipid droplet formation during ESC differentiation; Tnfaip2 KO impairs differentiation and lipid droplet induction, and supplementation with palmitic acid rescues this defect. Knockout mouse ESCs, lipid profiling, epistasis analysis, rescue with palmitic acid EMBO reports Medium 33300287
2023 Crystallization of truncated human Sec6 (HuSec6 121-734 and 121-745) was achieved with >95% purity, yielding crystals with ~9 Å X-ray diffraction, providing a structural foundation for analysis of human EXOC3. Recombinant protein expression in E. coli, purification, X-ray crystallography Studies in health technology and informatics Low 38007759
2024 Male germline-specific conditional knockout of Exoc3 (EXOC3/SEC6) in mice does not disrupt spermatogenesis, establishing that EXOC3 is dispensable for this process (unlike EXOC1/SEC3 or EXOC7/EXO70). Conditional knockout (Cre-lox), histological analysis of spermatogenesis Experimental animals Medium 38325858

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell 434 9630218
1998 Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments. Neuron 296 9655500
1995 Sec6, Sec8, and Sec15 are components of a multisubunit complex which localizes to small bud tips in Saccharomyces cerevisiae. The Journal of cell biology 257 7615633
2005 Drosophila exocyst components Sec5, Sec6, and Sec15 regulate DE-Cadherin trafficking from recycling endosomes to the plasma membrane. Developmental cell 231 16224820
2001 Sec6/8 complexes on trans-Golgi network and plasma membrane regulate late stages of exocytosis in mammalian cells. The Journal of cell biology 147 11696560
2004 Mechanism of recruiting Sec6/8 (exocyst) complex to the apical junctional complex during polarization of epithelial cells. Journal of cell science 142 14709721
2008 Sec6-dependent sorting of fungal extracellular exosomes and laccase of Cryptococcus neoformans. Molecular microbiology 129 19210702
1999 Targeting vesicles to specific sites on the plasma membrane: the role of the sec6/8 complex. Trends in cell biology 125 10203793
2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 122 15920473
2005 Essential function of Drosophila Sec6 in apical exocytosis of epithelial photoreceptor cells. The Journal of cell biology 101 15897260
2003 Structural basis of the interaction between RalA and Sec5, a subunit of the sec6/8 complex. The EMBO journal 98 12839989
2001 The Sec6/8 complex in mammalian cells: characterization of mammalian Sec3, subunit interactions, and expression of subunits in polarized cells. Proceedings of the National Academy of Sciences of the United States of America 95 11493706
2011 Regulation of exocytosis by the exocyst subunit Sec6 and the SM protein Sec1. Molecular biology of the cell 86 22114349
2000 The mammalian Sec6/8 complex interacts with Ca(2+) signaling complexes and regulates their activity. The Journal of cell biology 81 10973998
2013 Regulation of cytokinesis by exocyst subunit SEC6 and KEULE in Arabidopsis thaliana. Molecular plant 52 23702595
2015 The Exocyst Subunit Sec6 Interacts with Assembled Exocytic SNARE Complexes. The Journal of biological chemistry 45 26446795
1992 SEC6 encodes an 85 kDa soluble protein required for exocytosis in yeast. Yeast (Chichester, England) 31 1523887
2003 Sec6 is localized to the plasma membrane of mature synaptic terminals and is transported with secretogranin II-containing vesicles. Neuroscience 30 12763070
2003 Ultracentrifugation-based approaches to study regulation of Sec6/8 (exocyst) complex function during development of epithelial cell polarity. Methods (San Diego, Calif.) 26 12798134
2012 The SEC6 protein is required for contractile vacuole function in Chlamydomonas reinhardtii. Journal of cell science 21 22427688
2018 Sec6 enhances cell migration and suppresses apoptosis by elevating the phosphorylation of p38 MAPK, MK2, and HSP27. Cellular signalling 20 29729335
2016 Nuclear Translocation of p65 is Controlled by Sec6 via the Degradation of IκBα. Journal of cellular physiology 19 26247921
2020 Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis. EMBO reports 17 33300287
2016 Mutations in exocyst complex subunit SEC6 gene impaired polar auxin transport and PIN protein recycling in Arabidopsis primary root. Plant science : an international journal of experimental plant biology 16 27457987
2014 Sec6 regulated cytoplasmic translocation and degradation of p27 via interactions with Jab1 and Siah1. Cellular signalling 16 24949832
2012 Knockdown of Sec6 improves cell-cell adhesion by increasing α-E-catenin in oral cancer cells. FEBS letters 16 22381337
2015 Role of the Exocyst Complex Component Sec6/8 in Genomic Stability. Molecular and cellular biology 15 26283729
2005 Characterization of the Saccharomyces cerevisiae sec6-4 mutation and tools to create S. cerevisiae strains containing the sec6-4 allele. Gene 14 16185821
2016 Sec6/8 regulates Bcl-2 and Mcl-1, but not Bcl-xl, in malignant peripheral nerve sheath tumor cells. Apoptosis : an international journal on programmed cell death 13 26892009
2021 Loss of the exocyst complex component EXOC3 promotes hemostasis and accelerates arterial thrombosis. Blood advances 12 33560379
2019 Exocyst subunit Sec6 is positioned by microtubule overlaps in the moss phragmoplast prior to cell plate membrane arrival. Journal of cell science 12 30635445
2008 Involvement of Exoc3l, a protein structurally related to the exocyst subunit Sec6, in insulin secretion. Biomedical research (Tokyo, Japan) 12 18480549
2015 The Candida albicans Exocyst Subunit Sec6 Contributes to Cell Wall Integrity and Is a Determinant of Hyphal Branching. Eukaryotic cell 8 26002719
2022 Molecular cloning, inducible expression and function analysis of Epinephelus coioides Sec6 response to SGIV infection. Fish & shellfish immunology 7 35483595
2021 SEC6 exocyst subunit contributes to multiple steps of growth and development of Physcomitrella (Physcomitrium patens). The Plant journal : for cell and molecular biology 7 33599020
2022 Arabidopsis exocyst subunit SEC6 is involved in cell plate formation during Microgametogenesis. Biochemical and biophysical research communications 6 35151976
2023 SEC1A and SEC6 synergistically regulate pollen tube polar growth. Journal of integrative plant biology 5 36951316
2024 Deletion of Exoc7, but not Exoc3, in male germ cells causes severe spermatogenesis failure with spermatocyte aggregation in mice. Experimental animals 1 38325858
2025 Sec6 suppresses BEFV-triggered type I IFN responses by promoting P62-mediated MAVS degradation. Veterinary microbiology 0 40780029
2025 Sec6 suppresses BoHV-1-triggered innate immunity through NDP52-mediated autophagic degradation of STING. Veterinary microbiology 0 41406560
2023 Structural Study of the Exocyst Subunit Human Sec6. Studies in health technology and informatics 0 38007759