{"gene":"EXOC3","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"SEC6 encodes an 85 kDa predominantly soluble protein that sediments at 14S and is required for fusion of post-Golgi vesicles with the plasma membrane in S. cerevisiae; sec6-4 displays synthetic lethality with sec8-9, indicating inter-related functions between the two gene products.","method":"Gene cloning by complementation, subcellular fractionation, gene disruption, synthetic lethality analysis","journal":"Yeast","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods in foundational yeast study, replicated by subsequent complex characterization papers","pmids":["1523887"],"is_preprint":false},{"year":1995,"finding":"Sec6 is a stable component of the yeast Sec6/8/15 multisubunit complex (~1-2 MDa); Sec6 co-fractionates with Sec8/15 by metal-affinity chromatography, gel filtration, and sucrose velocity centrifugation, and coimmunoprecipitates with c-myc-tagged Sec8. The complex is disrupted in sec3-2, sec5-24, and sec10-2 backgrounds. Sec8 localizes to small bud tips, placing the complex at sites of exocytosis.","method":"Immobilized metal affinity chromatography, gel filtration, sucrose velocity centrifugation, immunoprecipitation, immunofluorescence localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods plus localization, replicated across subsequent studies","pmids":["7615633"],"is_preprint":false},{"year":1998,"finding":"In mammalian epithelial (MDCK) cells, the Sec6/8 complex resides in a cytosolic ~17S complex; upon calcium-dependent cell-cell adhesion, ~70% of Sec6/8 is recruited to sites of cell-cell contact. Sec8 antibodies in permeabilized cells inhibit delivery of LDL receptor to the basal-lateral membrane but not p75NTR to the apical membrane, demonstrating that lateral membrane recruitment of the Sec6/8 complex is essential for biogenesis of epithelial cell surface polarity.","method":"Sucrose gradient sedimentation, streptolysin-O permeabilization with antibody inhibition, immunofluorescence","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including functional antibody inhibition assay with specific cargo readouts, replicated in subsequent studies","pmids":["9630218"],"is_preprint":false},{"year":1998,"finding":"The rat brain sec6/8 complex coimmunoprecipitates with a filament composed of four mammalian septins (including CDC10), suggesting a physical interaction between the exocyst and septin filaments. Electron microscopy of glutaraldehyde-fixed rat brain sec6/8 complex reveals a T- or Y-shaped conformation.","method":"Co-immunoprecipitation, electron microscopy, sucrose gradient fractionation","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus EM structural characterization in single study; interaction functionally unresolved","pmids":["9655500"],"is_preprint":false},{"year":2001,"finding":"Sec6/8 complex is present on both the trans-Golgi network (TGN) and plasma membrane in NRK cells, colocalizing with exocytic cargo VSVG-tsO45. Brefeldin A blocks Sec6/8 recruitment to the plasma membrane; expression of kinase-inactive protein kinase D or low-temperature incubation causes Sec6/8 accumulation on TGN. Antibodies against TGN-bound or plasma membrane-bound Sec6/8 added to semiintact cells cause cargo accumulation in respective compartments, indicating Sec6/8 is required for multiple steps of TGN-to-plasma membrane exocytic transport.","method":"Immunofluorescence colocalization, semiintact cell functional assays with specific antibody inhibition, pharmacological treatments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional antibody inhibition in semiintact cells combined with pharmacological dissection, multiple orthogonal approaches","pmids":["11696560"],"is_preprint":false},{"year":2001,"finding":"Human Sec3 (hSec3) interacts with Sec5 and Sec8 subunits of the mammalian Sec6/8 complex in the yeast two-hybrid system. GFP-fusions of most subunits fail to assemble into complex with endogenous proteins and are cytosolic when expressed in MDCK cells; only GFP-Exo70 localizes to lateral membrane, and its overexpression disrupts tight monolayer formation.","method":"Yeast two-hybrid, GFP fusion expression and imaging in MDCK cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid for interactions; GFP localization for Exo70 phenotype; single lab, two methods","pmids":["11493706"],"is_preprint":false},{"year":2000,"finding":"Sec6/8 complex associates with Ca2+ signaling proteins at the apical pole of pancreatic acinar cells. Immunoprecipitation of Sec8 co-precipitates Sec6, IP3R3, Gβγ, plasma membrane Ca2+ pump, Gαq, PLCβ1, and IP3R1. This interaction is mediated by the actin cytoskeleton, as actin filament disruption dissociates Sec6/8 from Ca2+ signaling proteins. Anti-Sec6/8 antibodies inhibit Ca2+ signaling upstream of Ca2+ release by IP3; actin disruption by latrunculin B partially translocates Sec6/8 to cytosol and interferes with Ca2+ wave propagation.","method":"Immunoprecipitation, confocal immunolocalization, pharmacological actin disruption, functional Ca2+ signaling assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional inhibition assay; single lab, multiple methods","pmids":["10973998"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the Sec5 Ral-binding domain in complex with RalA·GppNHp at 2.1 Å resolution shows that Sec5 folds into an immunoglobulin-like β-sandwich and interacts with RalA via a continuous antiparallel β-sheet involving both switch regions. Sec5 Thr11 and Arg27, and RalA Glu38 are required for complex formation (validated by isothermal titration calorimetry). This establishes the structural basis for GTP-dependent RalA binding to the Sec6/8 complex via the Sec5 subunit.","method":"X-ray crystallography (2.1 Å), isothermal titration calorimetry, site-directed mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and ITC validation, rigorous single study","pmids":["12839989"],"is_preprint":false},{"year":2004,"finding":"In polarized MDCK epithelial cells, the Sec6/8 complex is recruited to cell-cell contacts in a high molecular mass complex with tight junction proteins and a portion of E-cadherin. Sec6/8 co-immunoprecipitates with cell surface-labeled E-cadherin and nectin-2α. Co-expression of E-cadherin and nectin-2α in fibroblasts is sufficient to recruit Sec6/8 to cell-cell contacts, indicating that adhesion complexes specify Sec6/8 localization.","method":"Co-immunoprecipitation, sucrose gradient fractionation, GFP overexpression in fibroblasts, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reconstitution in fibroblasts; single lab, two orthogonal methods","pmids":["14709721"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the Exo84 Ral-binding domain in complex with active RalA shows the domain adopts a pleckstrin homology fold. Structural and biochemical data demonstrate that Exo84 and Sec5 competitively bind active RalA via an overlapping interface including both switch regions; key binding residues were confirmed by mutagenesis. This establishes that RalA regulates Sec6/8 complex assembly through competitive effector binding.","method":"X-ray crystallography, site-directed mutagenesis, binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation and biochemical competition assay in single rigorous study","pmids":["15920473"],"is_preprint":false},{"year":2005,"finding":"In Drosophila photoreceptor cells (PRCs), loss-of-function sec6 mutations cause cell lethality, disrupt plasma membrane growth, and lead to accumulation of secretory vesicles and failure to transport proteins to the rhabdomere (apical subdomain). Sec6 but not Sec5 or Sec8 shows accumulation at adherens junctions in developing PRCs. Rab11 forms a complex with Sec5, and Sec5 interacts with Sec6, suggesting the exocyst is a Rab11 effector for apical membrane protein transport.","method":"Genetic loss-of-function analysis, immunofluorescence localization, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic LOF with specific cargo trafficking phenotype plus co-IP for complex interaction, multiple orthogonal methods","pmids":["15897260"],"is_preprint":false},{"year":2005,"finding":"In Drosophila epithelial cells, loss of function of exocyst components sec5, sec6, and sec15 causes DE-Cadherin accumulation in an enlarged Rab11 recycling endosomal compartment and inhibits DE-Cad delivery to the plasma membrane. Rab11 and Armadillo interact with exocyst components Sec15 and Sec10 respectively, placing Sec6-containing exocyst complex at the step of Rab11 recycling endosome-to-membrane trafficking.","method":"Genetic loss-of-function, immunofluorescence, co-immunoprecipitation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic LOF with defined trafficking phenotype, co-IP for protein interactions, multiple orthogonal methods","pmids":["16224820"],"is_preprint":false},{"year":2005,"finding":"The sec6-4 phenotype in S. cerevisiae is defined by a single point mutation L633P in the SEC6 coding region. At restrictive temperature, Sec6-4p is mislocalized and cells accumulate homogeneous secretory vesicles. At permissive temperature, wild-type Sec6p-GFP localizes to buds and septa, consistent with its role at sites of exocytosis.","method":"Site-directed mutagenesis, GFP fusion localization, electron microscopy of vesicle accumulation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis defining causal mutation plus GFP localization; single lab","pmids":["16185821"],"is_preprint":false},{"year":2011,"finding":"Yeast Sec6 directly binds Sec1 (a Sec1/Munc18 family SM protein) in addition to its known binding partner Sec9 (plasma membrane SNARE). The Sec6-Sec1 interaction is exclusive of Sec6-Sec9 but compatible with Sec6-exocyst assembly. The Sec6-exocyst interaction is incompatible with Sec6-Sec9. This proposes a sequential mechanism whereby vesicle arrival triggers Sec6 to release Sec9, assemble into exocyst, and recruit Sec1 for coordinated SNARE complex formation.","method":"In vitro binding assays, co-immunoprecipitation, yeast genetics","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro binding assays establishing mutually exclusive interactions, complemented by co-IP and genetic analysis","pmids":["22114349"],"is_preprint":false},{"year":2015,"finding":"S. cerevisiae Sec6 binds both the binary Sso1-Sec9 and ternary Sso1-Sec9-Snc2 SNARE complexes; it does not change the rate of SNARE assembly (contrary to previous hypothesis that it inhibits assembly). Cross-linking/mass spectrometry identified specific residues required for Sec6-Sec9 binding; mutation of these residues causes a yeast growth defect.","method":"In vitro SNARE assembly kinetic assays, cross-linking mass spectrometry, site-directed mutagenesis, yeast growth assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro SNARE assembly assays combined with cross-linking MS and mutagenesis with in vivo validation","pmids":["26446795"],"is_preprint":false},{"year":2012,"finding":"Sec6 knockdown in HSC3 oral cancer cells increases α-E-catenin expression and causes E-cadherin and β-catenin to localize predominantly at cell-cell contact regions, indicating Sec6 negatively regulates cell-cell adhesion complex organization.","method":"siRNA knockdown, immunofluorescence, western blot","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with immunofluorescence, no direct mechanistic pathway established","pmids":["22381337"],"is_preprint":false},{"year":2014,"finding":"Sec6 regulates cytoplasmic translocation and degradation of p27 via interactions with Jab1/CSN5 and Siah1; Sec6 promotes p27 phosphorylation at Thr157, facilitating cytoplasmic localization and subsequent degradation, thereby suppressing cell cycle progression.","method":"siRNA knockdown, co-immunoprecipitation, phosphorylation analysis, cell cycle assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interactions plus functional cell cycle phenotype; single lab, two orthogonal methods","pmids":["24949832"],"is_preprint":false},{"year":2015,"finding":"Perturbation of exocyst components including Sec6/8 results in resistance to ionizing radiation and accelerated resolution of DNA damage, but with accumulation of aberrant chromatid exchanges. Sec8 perturbation leads to accumulation of ATF2, RNF20, and DDR-associated chromatin marks, and Rad51 repairosomes, indicating exocyst supports DNA repair fidelity.","method":"siRNA knockdown, irradiation survival assays, chromatin immunoprecipitation, recombination frequency measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (DNA damage, chromatin marks, recombination) but mechanistic link between EXOC3 specifically and DDR is indirect; single lab","pmids":["26283729"],"is_preprint":false},{"year":2016,"finding":"Sec6 knockdown inhibits IκBα degradation, delays nuclear translocation of p65, and reduces NF-κB transcriptional activity in TNF-α-stimulated HeLa cells. Mechanistically, Sec6 knockdown decreases expression of p90RSKs and phosphorylation of ERK, p90RSK1 (Ser380), and IκBα (Ser32).","method":"siRNA knockdown, western blot for phosphorylation, luciferase transcriptional reporter, immunofluorescence for p65 localization","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with multiple phosphorylation and transcriptional readouts; single lab, indirect pathway placement","pmids":["26247921"],"is_preprint":false},{"year":2018,"finding":"Sec6 knockdown suppresses phosphorylation of p38 MAPK (via MKK3/6), MK2, and HSP27 (at Ser78 and Ser82), and overexpression has the reverse effect. Reduced phospho-HSP27 via Sec6 knockdown suppresses cell migration and promotes apoptosis after TNF-α/cycloheximide treatment.","method":"siRNA knockdown, overexpression, western blot for kinase phosphorylation, cell migration assays, apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with kinase phosphorylation readouts; single lab, multiple orthogonal functional assays","pmids":["29729335"],"is_preprint":false},{"year":2019,"finding":"In Physcomitrella patens, exocyst subunit Sec6 (but not Sec3 or Sec5) localizes to microtubule overlap regions in the phragmoplast prior to cell plate membrane arrival. Sec6 physically interacts with KEULE (a Sec1/Munc18 ortholog). Sec6 gene silencing delays recruitment of KEULE and vesicles to the early cell plate, indicating Sec6 promotes vesicle-vesicle fusion at microtubule overlaps independently of vesicle delivery.","method":"Live-cell fluorescence microscopy, co-immunoprecipitation, gene silencing, time-lapse imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging localization with functional gene silencing plus co-IP; plant ortholog study, single lab","pmids":["30635445"],"is_preprint":false},{"year":2020,"finding":"Tnfaip2/Exoc3 acts epistatically upstream of vimentin (Vim) in controlling lipid metabolism during stem cell differentiation; Tnfaip2 knockout impairs induction of triacylglycerol synthesis and lipid droplet formation in differentiating ESCs. Knockdown of planarian Smed-exoc3 also causes strong reduction of TAGs. Supplementation with palmitic acid rescues both ESC differentiation and planarian organ maintenance, placing Exoc3 upstream of TAG/lipid droplet biosynthesis required for differentiation.","method":"Genetic knockout/knockdown, lipidomics, epistasis analysis, rescue with palmitic acid supplementation","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two independent model systems (mouse ESCs and planarians) with metabolic rescue; single lab","pmids":["33300287"],"is_preprint":false},{"year":2021,"finding":"EXOC3 conditional knockout in mouse megakaryocytes/platelets causes defects in platelet aggregation, integrin activation, α-granule secretion (P-selectin, PF4), dense granule secretion, and lysosomal granule secretion after GPVI agonist stimulation. GPVI surface levels were decreased 14.5% in KO platelets, with defects in proximal GPVI signaling (Syk and LAT phosphorylation) and calcium mobilization. PAR4-stimulated responses were paradoxically enhanced in KO platelets, and suppressed by P2Y12 antagonist, implicating enhanced ADP release. EXOC3 KO mice show accelerated arterial thrombosis and improved hemostasis.","method":"Conditional knockout mice, platelet aggregometry, granule secretion assays, flow cytometry, phosphorylation analysis, calcium imaging, in vivo thrombosis model, tail bleeding time","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with multiple orthogonal functional readouts including signaling, secretion, and in vivo thrombosis","pmids":["33560379"],"is_preprint":false},{"year":2023,"finding":"Two truncated forms of human Sec6 (HuSec6 121-734 and HuSec6 121-745) were expressed, purified (>95% purity), and crystallized; X-ray diffraction yielded ~9 Å resolution crystals, providing initial structural data for human Sec6.","method":"Recombinant protein expression in E. coli, X-ray crystallography (9 Å resolution)","journal":"Studies in health technology and informatics","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallography initiated but only low-resolution diffraction reported; no functional validation; single preliminary study","pmids":["38007759"],"is_preprint":false},{"year":2024,"finding":"Male germ cell-specific conditional knockout of Exoc3 (SEC6) in mice does not cause spermatogenesis defects, establishing that EXOC3 is not required for spermatogenesis (negative finding).","method":"Conditional knockout mice, histological analysis of spermatogenesis","journal":"Experimental animals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined negative phenotypic readout; single study","pmids":["38325858"],"is_preprint":false},{"year":2025,"finding":"Sec6 suppresses innate immune responses to bovine herpesvirus 1 (BoHV-1) by promoting NDP52-mediated autophagic degradation of STING. Mechanistically, Sec6 enhances the physical interaction between NDP52 and STING; NDP52 knockdown abolishes Sec6-mediated IFN-β suppression and Sec6's ability to enhance viral replication.","method":"Overexpression/knockdown, co-immunoprecipitation, autophagic flux assays, IFN-β reporter assay, viral replication assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interaction plus epistasis (NDP52 KD rescues phenotype); single lab, bovine cell model","pmids":["41406560"],"is_preprint":false},{"year":2025,"finding":"Sec6 suppresses BEFV-triggered type I IFN signaling by promoting P62-mediated autophagic degradation of MAVS. Sec6 enhances the P62-MAVS interaction; P62 knockdown abolishes Sec6-mediated IFN-I suppression and viral replication enhancement. Sec6 fails to degrade MAVS in P62-knockdown cells.","method":"Overexpression/knockdown, co-immunoprecipitation, autophagic flux assays, IFN-I reporter assay, viral replication assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus epistasis (P62 KD); single lab, bovine cell model","pmids":["40780029"],"is_preprint":false}],"current_model":"EXOC3/Sec6 is a core subunit of the octameric exocyst tethering complex that physically associates with other exocyst subunits (Sec8, Sec15, etc.) and directly binds SNARE proteins (Sec9/Sso1 complexes) and the SM protein Sec1/Munc18 to coordinate secretory vesicle tethering and SNARE-mediated fusion at the plasma membrane; in polarized epithelial cells it is recruited to cell-cell contact sites via E-cadherin and nectin adhesion complexes to direct basolateral exocytic traffic, in neurons it localizes to presynaptic membranes, and in platelets it is required for granule secretion and GPVI signaling; it also engages RalA GTPase signaling (via competitive Sec5/Exo84 effector binding), modulates p38 MAPK-MK2-HSP27 and NF-κB/IκBα signaling cascades, controls lipid metabolism upstream of vimentin during stem cell differentiation, and can promote autophagic degradation of innate immune adaptors STING and MAVS."},"narrative":{"mechanistic_narrative":"EXOC3/Sec6 is a core subunit of the octameric exocyst, a multisubunit tethering complex that directs secretory vesicle delivery and fusion at the plasma membrane [PMID:1523887, PMID:7615633]. First defined in budding yeast as a soluble ~85 kDa protein required for fusion of post-Golgi vesicles, Sec6 is a stable component of the ~1–2 MDa Sec6/8/15 complex that localizes to sites of active exocytosis [PMID:1523887, PMID:7615633]. In mammalian cells the complex cycles between a cytosolic pool and membrane-recruited states, residing on both the trans-Golgi network and plasma membrane and being required for multiple steps of TGN-to-plasma-membrane exocytic transport [PMID:11696560]. In polarized epithelia, calcium-dependent cell-cell adhesion recruits the complex to lateral contacts in association with E-cadherin and nectin-2α and tight junction proteins, a localization sufficient to direct basolateral surface biogenesis [PMID:9630218, PMID:14709721]. Mechanistically, Sec6 couples tethering to SNARE-mediated fusion: it directly and mutually exclusively binds the plasma membrane SNARE Sec9 and the Sec1/Munc18 SM protein Sec1, binds binary and ternary Sso1-Sec9-Snc2 SNARE complexes, and engages the exocyst itself in a manner incompatible with Sec9 binding, supporting a sequential hand-off model upon vesicle arrival [PMID:22114349, PMID:26446795]. The complex is regulated by the small GTPase RalA, which binds the Sec5 and Exo84 subunits competitively through overlapping switch-region interfaces to control complex assembly [PMID:12839989, PMID:15920473]. Beyond canonical secretion, EXOC3 supports developmental and physiological trafficking demonstrated genetically across systems: it acts as a Rab11-recycling-endosome effector for apical and adherens-junction cargo delivery in Drosophila [PMID:15897260, PMID:16224820], is required for platelet granule secretion, integrin activation and GPVI signaling with consequences for thrombosis and hemostasis [PMID:33560379], and acts upstream of vimentin to control triacylglycerol/lipid-droplet biosynthesis during stem cell differentiation [PMID:33300287]. EXOC3 also negatively regulates innate antiviral immunity by promoting selective-autophagy receptor–mediated degradation of the adaptors STING (via NDP52) and MAVS (via P62) [PMID:41406560, PMID:40780029].","teleology":[{"year":1992,"claim":"Established that Sec6 is a discrete gene product essential for the terminal step of secretion, answering whether post-Golgi vesicle fusion at the plasma membrane requires a dedicated soluble factor.","evidence":"Gene cloning by complementation, fractionation, and synthetic lethality with sec8 in S. cerevisiae","pmids":["1523887"],"confidence":"High","gaps":["No biochemical complex defined","No molecular partners or mechanism of action identified"]},{"year":1995,"claim":"Defined Sec6 as a stable subunit of a large multiprotein assembly localized to exocytic sites, transforming it from an isolated gene into a complex component.","evidence":"Affinity chromatography, gel filtration, sucrose gradients, co-IP, and immunofluorescence in yeast","pmids":["7615633"],"confidence":"High","gaps":["Subunit stoichiometry and architecture unresolved","Direct molecular activity of Sec6 within the complex unknown"]},{"year":2000,"claim":"Extended exocyst function to mammalian polarized trafficking and signaling-organelle scaffolding, showing the complex is recruited to membrane domains and links to adhesion and Ca2+ machinery.","evidence":"Permeabilized-cell antibody inhibition with cargo readouts in MDCK cells; reciprocal co-IP and Ca2+ assays in pancreatic acinar cells","pmids":["9630218","10973998"],"confidence":"High","gaps":["Which subunit mediates membrane recruitment not resolved","Ca2+-protein associations are correlative, mechanism indirect"]},{"year":2001,"claim":"Mapped exocyst itinerary and intra-complex interactions, showing the complex functions at both TGN and plasma membrane steps of exocytosis.","evidence":"Semiintact-cell antibody inhibition with pharmacology in NRK cells; yeast two-hybrid mapping of human subunit contacts","pmids":["11696560","11493706"],"confidence":"High","gaps":["Sec6-specific contribution to each step not isolated","GFP-subunit assembly failures leave human complex architecture unclear"]},{"year":2004,"claim":"Identified the molecular cue specifying exocyst localization in epithelia, answering how the complex finds lateral membrane domains.","evidence":"Co-IP with surface-labeled E-cadherin/nectin-2α and reconstitution in fibroblasts (MDCK system)","pmids":["14709721"],"confidence":"Medium","gaps":["Direct vs indirect binding to cadherin/nectin not distinguished","Subunit responsible for adhesion-complex contact unknown"]},{"year":2005,"claim":"Provided structural and genetic mechanism for GTPase regulation and developmental cargo trafficking, establishing RalA as a competitive regulator and the exocyst as a Rab11 effector.","evidence":"Crystallography of Exo84-RalA with competition assays; Drosophila sec6 loss-of-function with cargo trafficking phenotypes and co-IP","pmids":["15920473","15897260","16224820"],"confidence":"High","gaps":["RalA regulation maps to Sec5/Exo84, not Sec6 directly","How Rab11 endosome trafficking integrates with SNARE fusion unresolved"]},{"year":2015,"claim":"Resolved how Sec6 couples tethering to fusion machinery, showing direct, mutually exclusive binding to SNARE and SM proteins that orders assembly events.","evidence":"In vitro binding/SNARE-assembly kinetics, cross-linking MS, and mutagenesis with yeast growth validation","pmids":["22114349","26446795"],"confidence":"High","gaps":["Sequential hand-off model not directly visualized on vesicles","Conservation of Sec6-SM/SNARE coupling in mammals not demonstrated"]},{"year":2019,"claim":"Demonstrated a vesicle-vesicle fusion role at cytoskeletal sites independent of delivery, broadening Sec6 function beyond plasma-membrane tethering.","evidence":"Live imaging, gene silencing, and co-IP with KEULE in Physcomitrella patens phragmoplast","pmids":["30635445"],"confidence":"Medium","gaps":["Plant-ortholog finding; mammalian relevance untested","Mechanism of microtubule-overlap targeting unknown"]},{"year":2021,"claim":"Established a physiological secretory requirement in mammals in vivo, showing EXOC3 is essential for platelet granule secretion and receptor signaling with thrombotic consequences.","evidence":"Conditional knockout mice with aggregometry, secretion assays, signaling readouts, and in vivo thrombosis/bleeding models","pmids":["33560379"],"confidence":"High","gaps":["Whether defects reflect canonical exocyst tethering or additional roles not dissected","Mechanism of paradoxical PAR4 enhancement only partially explained"]},{"year":2020,"claim":"Linked EXOC3 to lipid metabolism in differentiation, placing it upstream of vimentin in controlling TAG/lipid-droplet biosynthesis.","evidence":"Genetic knockout/knockdown, lipidomics, epistasis, and palmitic acid rescue in mouse ESCs and planarians","pmids":["33300287"],"confidence":"Medium","gaps":["Molecular link between exocyst tethering and lipid synthesis not defined","Whether function requires exocyst complex unknown"]},{"year":2025,"claim":"Identified a function in innate immune suppression, showing EXOC3 promotes selective autophagic degradation of antiviral adaptors.","evidence":"Overexpression/knockdown, co-IP, autophagic flux, IFN reporters, and viral replication assays with NDP52/P62 epistasis in bovine cells","pmids":["41406560","40780029"],"confidence":"Medium","gaps":["Single-lab, bovine cell models","Whether degradation requires the intact exocyst complex untested","Direct vs scaffold role in receptor-adaptor recruitment unresolved"]},{"year":null,"claim":"How EXOC3 mechanistically bridges its canonical exocyst tethering/SNARE-coupling activity with the diverse signaling, metabolic, and autophagy phenotypes attributed to it in mammalian systems remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of human Sec6 or the assembled human exocyst","Whether non-secretory roles depend on the intact complex untested","Direct binding partners for mammalian signaling/autophagy functions not biochemically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,4]}],"complexes":["exocyst (Sec6/8/15 complex)"],"partners":["EXOC4","EXOC6","SEC9","SEC1","RALA","CDH1","RAB11","NDP52"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60645","full_name":"Exocyst complex component 3","aliases":["Exocyst complex component Sec6"],"length_aa":745,"mass_kda":85.6,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Cell projection, growth cone; Midbody; Golgi apparatus; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/O60645/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC3","classification":"Common Essential","n_dependent_lines":962,"n_total_lines":1208,"dependency_fraction":0.7963576158940397},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EXOC3","total_profiled":1310},"omim":[{"mim_id":"621085","title":"EXOCYST COMPLEX COMPONENT 3-LIKE 4; EXOC3L4","url":"https://www.omim.org/entry/621085"},{"mim_id":"616927","title":"EXOCYST COMPLEX COMPONENT 3-LIKE 2; EXOC3L2","url":"https://www.omim.org/entry/616927"},{"mim_id":"614117","title":"EXOCYST COMPLEX COMPONENT 3-LIKE 1; EXOC3L1","url":"https://www.omim.org/entry/614117"},{"mim_id":"608186","title":"EXOCYST COMPLEX COMPONENT 3; EXOC3","url":"https://www.omim.org/entry/608186"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOC3"},"hgnc":{"alias_symbol":["Sec6"],"prev_symbol":["SEC6L1"]},"alphafold":{"accession":"O60645","domains":[{"cath_id":"-","chopping":"33-243","consensus_level":"medium","plddt":86.6618,"start":33,"end":243},{"cath_id":"-","chopping":"248-372","consensus_level":"medium","plddt":94.1593,"start":248,"end":372},{"cath_id":"1.10.357.50","chopping":"377-540","consensus_level":"high","plddt":91.4301,"start":377,"end":540},{"cath_id":"1.10.357.70","chopping":"558-733","consensus_level":"high","plddt":88.592,"start":558,"end":733}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60645","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60645-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60645-F1-predicted_aligned_error_v6.png","plddt_mean":88.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOC3","jax_strain_url":"https://www.jax.org/strain/search?query=EXOC3"},"sequence":{"accession":"O60645","fasta_url":"https://rest.uniprot.org/uniprotkb/O60645.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60645/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60645"}},"corpus_meta":[{"pmid":"9630218","id":"PMC_9630218","title":"Sec6/8 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signalling","url":"https://pubmed.ncbi.nlm.nih.gov/29729335","citation_count":20,"is_preprint":false},{"pmid":"26247921","id":"PMC_26247921","title":"Nuclear Translocation of p65 is Controlled by Sec6 via the Degradation of IκBα.","date":"2016","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26247921","citation_count":19,"is_preprint":false},{"pmid":"33300287","id":"PMC_33300287","title":"Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33300287","citation_count":17,"is_preprint":false},{"pmid":"22381337","id":"PMC_22381337","title":"Knockdown of Sec6 improves cell-cell adhesion by increasing α-E-catenin in oral cancer cells.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/22381337","citation_count":16,"is_preprint":false},{"pmid":"24949832","id":"PMC_24949832","title":"Sec6 regulated cytoplasmic translocation and degradation of p27 via interactions with Jab1 and Siah1.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24949832","citation_count":16,"is_preprint":false},{"pmid":"26283729","id":"PMC_26283729","title":"Role of the Exocyst Complex Component Sec6/8 in Genomic Stability.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26283729","citation_count":15,"is_preprint":false},{"pmid":"16185821","id":"PMC_16185821","title":"Characterization of the Saccharomyces cerevisiae sec6-4 mutation and tools to create S. cerevisiae strains containing the sec6-4 allele.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16185821","citation_count":14,"is_preprint":false},{"pmid":"26892009","id":"PMC_26892009","title":"Sec6/8 regulates Bcl-2 and Mcl-1, but not Bcl-xl, in malignant peripheral nerve sheath tumor cells.","date":"2016","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/26892009","citation_count":13,"is_preprint":false},{"pmid":"30635445","id":"PMC_30635445","title":"Exocyst subunit Sec6 is positioned by microtubule overlaps in the moss phragmoplast prior to cell plate membrane arrival.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30635445","citation_count":13,"is_preprint":false},{"pmid":"33560379","id":"PMC_33560379","title":"Loss of the exocyst complex component EXOC3 promotes hemostasis and accelerates arterial thrombosis.","date":"2021","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33560379","citation_count":12,"is_preprint":false},{"pmid":"18480549","id":"PMC_18480549","title":"Involvement of Exoc3l, a protein structurally related to the exocyst subunit Sec6, in insulin secretion.","date":"2008","source":"Biomedical research (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/18480549","citation_count":12,"is_preprint":false},{"pmid":"35483595","id":"PMC_35483595","title":"Molecular cloning, inducible expression and function analysis of Epinephelus coioides Sec6 response to SGIV infection.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35483595","citation_count":8,"is_preprint":false},{"pmid":"26002719","id":"PMC_26002719","title":"The Candida albicans Exocyst Subunit Sec6 Contributes to Cell Wall Integrity and Is a Determinant of Hyphal Branching.","date":"2015","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/26002719","citation_count":8,"is_preprint":false},{"pmid":"33599020","id":"PMC_33599020","title":"SEC6 exocyst subunit contributes to multiple steps of growth and development of Physcomitrella (Physcomitrium patens).","date":"2021","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33599020","citation_count":7,"is_preprint":false},{"pmid":"36951316","id":"PMC_36951316","title":"SEC1A and SEC6 synergistically regulate pollen tube polar growth.","date":"2023","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/36951316","citation_count":6,"is_preprint":false},{"pmid":"41406560","id":"PMC_41406560","title":"Sec6 suppresses BoHV-1-triggered innate immunity through NDP52-mediated autophagic degradation of STING.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41406560","citation_count":2,"is_preprint":false},{"pmid":"40780029","id":"PMC_40780029","title":"Sec6 suppresses BEFV-triggered type I IFN responses by promoting P62-mediated MAVS degradation.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40780029","citation_count":1,"is_preprint":false},{"pmid":"38325858","id":"PMC_38325858","title":"Deletion of Exoc7, but not Exoc3, in male germ cells causes severe spermatogenesis failure with spermatocyte aggregation in mice.","date":"2024","source":"Experimental animals","url":"https://pubmed.ncbi.nlm.nih.gov/38325858","citation_count":1,"is_preprint":false},{"pmid":"38007759","id":"PMC_38007759","title":"Structural Study of the Exocyst Subunit Human Sec6.","date":"2023","source":"Studies in health technology and informatics","url":"https://pubmed.ncbi.nlm.nih.gov/38007759","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.31.684064","title":"Beyond reference bias: Making pangenomes accessible with PangyPlot","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.31.684064","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.30.667757","title":"The Drosophila ovarian terminal filament imports lipophilic molecules that regulate follicle development within its 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subcellular fractionation, gene disruption, synthetic lethality analysis\",\n \"journal\": \"Yeast\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical methods in foundational yeast study, replicated by subsequent complex characterization papers\",\n \"pmids\": [\"1523887\"],\n \"is_preprint\": false\n },\n {\n \"year\": 1995,\n \"finding\": \"Sec6 is a stable component of the yeast Sec6/8/15 multisubunit complex (~1-2 MDa); Sec6 co-fractionates with Sec8/15 by metal-affinity chromatography, gel filtration, and sucrose velocity centrifugation, and coimmunoprecipitates with c-myc-tagged Sec8. The complex is disrupted in sec3-2, sec5-24, and sec10-2 backgrounds. Sec8 localizes to small bud tips, placing the complex at sites of exocytosis.\",\n \"method\": \"Immobilized metal affinity chromatography, gel filtration, sucrose velocity centrifugation, immunoprecipitation, immunofluorescence localization\",\n \"journal\": \"The Journal of cell biology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods plus localization, replicated across subsequent studies\",\n \"pmids\": [\"7615633\"],\n \"is_preprint\": false\n },\n {\n \"year\": 1998,\n \"finding\": \"In mammalian epithelial (MDCK) cells, the Sec6/8 complex resides in a cytosolic ~17S complex; upon calcium-dependent cell-cell adhesion, ~70% of Sec6/8 is recruited to sites of cell-cell contact. Sec8 antibodies in permeabilized cells inhibit delivery of LDL receptor to the basal-lateral membrane but not p75NTR to the apical membrane, demonstrating that lateral membrane recruitment of the Sec6/8 complex is essential for biogenesis of epithelial cell surface polarity.\",\n \"method\": \"Sucrose gradient sedimentation, streptolysin-O permeabilization with antibody inhibition, immunofluorescence\",\n \"journal\": \"Cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including functional antibody inhibition assay with specific cargo readouts, replicated in subsequent studies\",\n \"pmids\": [\"9630218\"],\n \"is_preprint\": false\n },\n {\n \"year\": 1998,\n \"finding\": \"The rat brain sec6/8 complex coimmunoprecipitates with a filament composed of four mammalian septins (including CDC10), suggesting a physical interaction between the exocyst and septin filaments. Electron microscopy of glutaraldehyde-fixed rat brain sec6/8 complex reveals a T- or Y-shaped conformation.\",\n \"method\": \"Co-immunoprecipitation, electron microscopy, sucrose gradient fractionation\",\n \"journal\": \"Neuron\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus EM structural characterization in single study; interaction functionally unresolved\",\n \"pmids\": [\"9655500\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2001,\n \"finding\": \"Sec6/8 complex is present on both the trans-Golgi network (TGN) and plasma membrane in NRK cells, colocalizing with exocytic cargo VSVG-tsO45. Brefeldin A blocks Sec6/8 recruitment to the plasma membrane; expression of kinase-inactive protein kinase D or low-temperature incubation causes Sec6/8 accumulation on TGN. Antibodies against TGN-bound or plasma membrane-bound Sec6/8 added to semiintact cells cause cargo accumulation in respective compartments, indicating Sec6/8 is required for multiple steps of TGN-to-plasma membrane exocytic transport.\",\n \"method\": \"Immunofluorescence colocalization, semiintact cell functional assays with specific antibody inhibition, pharmacological treatments\",\n \"journal\": \"The Journal of cell biology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — functional antibody inhibition in semiintact cells combined with pharmacological dissection, multiple orthogonal approaches\",\n \"pmids\": [\"11696560\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2001,\n \"finding\": \"Human Sec3 (hSec3) interacts with Sec5 and Sec8 subunits of the mammalian Sec6/8 complex in the yeast two-hybrid system. GFP-fusions of most subunits fail to assemble into complex with endogenous proteins and are cytosolic when expressed in MDCK cells; only GFP-Exo70 localizes to lateral membrane, and its overexpression disrupts tight monolayer formation.\",\n \"method\": \"Yeast two-hybrid, GFP fusion expression and imaging in MDCK cells\",\n \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid for interactions; GFP localization for Exo70 phenotype; single lab, two methods\",\n \"pmids\": [\"11493706\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2000,\n \"finding\": \"Sec6/8 complex associates with Ca2+ signaling proteins at the apical pole of pancreatic acinar cells. Immunoprecipitation of Sec8 co-precipitates Sec6, IP3R3, Gβγ, plasma membrane Ca2+ pump, Gαq, PLCβ1, and IP3R1. This interaction is mediated by the actin cytoskeleton, as actin filament disruption dissociates Sec6/8 from Ca2+ signaling proteins. Anti-Sec6/8 antibodies inhibit Ca2+ signaling upstream of Ca2+ release by IP3; actin disruption by latrunculin B partially translocates Sec6/8 to cytosol and interferes with Ca2+ wave propagation.\",\n \"method\": \"Immunoprecipitation, confocal immunolocalization, pharmacological actin disruption, functional Ca2+ signaling assays\",\n \"journal\": \"The Journal of cell biology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional inhibition assay; single lab, multiple methods\",\n \"pmids\": [\"10973998\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2003,\n \"finding\": \"Crystal structure of the Sec5 Ral-binding domain in complex with RalA·GppNHp at 2.1 Å resolution shows that Sec5 folds into an immunoglobulin-like β-sandwich and interacts with RalA via a continuous antiparallel β-sheet involving both switch regions. Sec5 Thr11 and Arg27, and RalA Glu38 are required for complex formation (validated by isothermal titration calorimetry). This establishes the structural basis for GTP-dependent RalA binding to the Sec6/8 complex via the Sec5 subunit.\",\n \"method\": \"X-ray crystallography (2.1 Å), isothermal titration calorimetry, site-directed mutagenesis\",\n \"journal\": \"The EMBO journal\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and ITC validation, rigorous single study\",\n \"pmids\": [\"12839989\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2004,\n \"finding\": \"In polarized MDCK epithelial cells, the Sec6/8 complex is recruited to cell-cell contacts in a high molecular mass complex with tight junction proteins and a portion of E-cadherin. Sec6/8 co-immunoprecipitates with cell surface-labeled E-cadherin and nectin-2α. Co-expression of E-cadherin and nectin-2α in fibroblasts is sufficient to recruit Sec6/8 to cell-cell contacts, indicating that adhesion complexes specify Sec6/8 localization.\",\n \"method\": \"Co-immunoprecipitation, sucrose gradient fractionation, GFP overexpression in fibroblasts, immunofluorescence\",\n \"journal\": \"Journal of cell science\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reconstitution in fibroblasts; single lab, two orthogonal methods\",\n \"pmids\": [\"14709721\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2005,\n \"finding\": \"Crystal structure of the Exo84 Ral-binding domain in complex with active RalA shows the domain adopts a pleckstrin homology fold. Structural and biochemical data demonstrate that Exo84 and Sec5 competitively bind active RalA via an overlapping interface including both switch regions; key binding residues were confirmed by mutagenesis. This establishes that RalA regulates Sec6/8 complex assembly through competitive effector binding.\",\n \"method\": \"X-ray crystallography, site-directed mutagenesis, binding assays\",\n \"journal\": \"The EMBO journal\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation and biochemical competition assay in single rigorous study\",\n \"pmids\": [\"15920473\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2005,\n \"finding\": \"In Drosophila photoreceptor cells (PRCs), loss-of-function sec6 mutations cause cell lethality, disrupt plasma membrane growth, and lead to accumulation of secretory vesicles and failure to transport proteins to the rhabdomere (apical subdomain). Sec6 but not Sec5 or Sec8 shows accumulation at adherens junctions in developing PRCs. Rab11 forms a complex with Sec5, and Sec5 interacts with Sec6, suggesting the exocyst is a Rab11 effector for apical membrane protein transport.\",\n \"method\": \"Genetic loss-of-function analysis, immunofluorescence localization, co-immunoprecipitation\",\n \"journal\": \"The Journal of cell biology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — genetic LOF with specific cargo trafficking phenotype plus co-IP for complex interaction, multiple orthogonal methods\",\n \"pmids\": [\"15897260\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2005,\n \"finding\": \"In Drosophila epithelial cells, loss of function of exocyst components sec5, sec6, and sec15 causes DE-Cadherin accumulation in an enlarged Rab11 recycling endosomal compartment and inhibits DE-Cad delivery to the plasma membrane. Rab11 and Armadillo interact with exocyst components Sec15 and Sec10 respectively, placing Sec6-containing exocyst complex at the step of Rab11 recycling endosome-to-membrane trafficking.\",\n \"method\": \"Genetic loss-of-function, immunofluorescence, co-immunoprecipitation\",\n \"journal\": \"Developmental cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — genetic LOF with defined trafficking phenotype, co-IP for protein interactions, multiple orthogonal methods\",\n \"pmids\": [\"16224820\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2005,\n \"finding\": \"The sec6-4 phenotype in S. cerevisiae is defined by a single point mutation L633P in the SEC6 coding region. At restrictive temperature, Sec6-4p is mislocalized and cells accumulate homogeneous secretory vesicles. At permissive temperature, wild-type Sec6p-GFP localizes to buds and septa, consistent with its role at sites of exocytosis.\",\n \"method\": \"Site-directed mutagenesis, GFP fusion localization, electron microscopy of vesicle accumulation\",\n \"journal\": \"Gene\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis defining causal mutation plus GFP localization; single lab\",\n \"pmids\": [\"16185821\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"Yeast Sec6 directly binds Sec1 (a Sec1/Munc18 family SM protein) in addition to its known binding partner Sec9 (plasma membrane SNARE). The Sec6-Sec1 interaction is exclusive of Sec6-Sec9 but compatible with Sec6-exocyst assembly. The Sec6-exocyst interaction is incompatible with Sec6-Sec9. This proposes a sequential mechanism whereby vesicle arrival triggers Sec6 to release Sec9, assemble into exocyst, and recruit Sec1 for coordinated SNARE complex formation.\",\n \"method\": \"In vitro binding assays, co-immunoprecipitation, yeast genetics\",\n \"journal\": \"Molecular biology of the cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro binding assays establishing mutually exclusive interactions, complemented by co-IP and genetic analysis\",\n \"pmids\": [\"22114349\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"S. cerevisiae Sec6 binds both the binary Sso1-Sec9 and ternary Sso1-Sec9-Snc2 SNARE complexes; it does not change the rate of SNARE assembly (contrary to previous hypothesis that it inhibits assembly). Cross-linking/mass spectrometry identified specific residues required for Sec6-Sec9 binding; mutation of these residues causes a yeast growth defect.\",\n \"method\": \"In vitro SNARE assembly kinetic assays, cross-linking mass spectrometry, site-directed mutagenesis, yeast growth assays\",\n \"journal\": \"The Journal of biological chemistry\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro SNARE assembly assays combined with cross-linking MS and mutagenesis with in vivo validation\",\n \"pmids\": [\"26446795\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"Sec6 knockdown in HSC3 oral cancer cells increases α-E-catenin expression and causes E-cadherin and β-catenin to localize predominantly at cell-cell contact regions, indicating Sec6 negatively regulates cell-cell adhesion complex organization.\",\n \"method\": \"siRNA knockdown, immunofluorescence, western blot\",\n \"journal\": \"FEBS letters\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with immunofluorescence, no direct mechanistic pathway established\",\n \"pmids\": [\"22381337\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2014,\n \"finding\": \"Sec6 regulates cytoplasmic translocation and degradation of p27 via interactions with Jab1/CSN5 and Siah1; Sec6 promotes p27 phosphorylation at Thr157, facilitating cytoplasmic localization and subsequent degradation, thereby suppressing cell cycle progression.\",\n \"method\": \"siRNA knockdown, co-immunoprecipitation, phosphorylation analysis, cell cycle assays\",\n \"journal\": \"Cellular signalling\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interactions plus functional cell cycle phenotype; single lab, two orthogonal methods\",\n \"pmids\": [\"24949832\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"Perturbation of exocyst components including Sec6/8 results in resistance to ionizing radiation and accelerated resolution of DNA damage, but with accumulation of aberrant chromatid exchanges. Sec8 perturbation leads to accumulation of ATF2, RNF20, and DDR-associated chromatin marks, and Rad51 repairosomes, indicating exocyst supports DNA repair fidelity.\",\n \"method\": \"siRNA knockdown, irradiation survival assays, chromatin immunoprecipitation, recombination frequency measurement\",\n \"journal\": \"Molecular and cellular biology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (DNA damage, chromatin marks, recombination) but mechanistic link between EXOC3 specifically and DDR is indirect; single lab\",\n \"pmids\": [\"26283729\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2016,\n \"finding\": \"Sec6 knockdown inhibits IκBα degradation, delays nuclear translocation of p65, and reduces NF-κB transcriptional activity in TNF-α-stimulated HeLa cells. Mechanistically, Sec6 knockdown decreases expression of p90RSKs and phosphorylation of ERK, p90RSK1 (Ser380), and IκBα (Ser32).\",\n \"method\": \"siRNA knockdown, western blot for phosphorylation, luciferase transcriptional reporter, immunofluorescence for p65 localization\",\n \"journal\": \"Journal of cellular physiology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with multiple phosphorylation and transcriptional readouts; single lab, indirect pathway placement\",\n \"pmids\": [\"26247921\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2018,\n \"finding\": \"Sec6 knockdown suppresses phosphorylation of p38 MAPK (via MKK3/6), MK2, and HSP27 (at Ser78 and Ser82), and overexpression has the reverse effect. Reduced phospho-HSP27 via Sec6 knockdown suppresses cell migration and promotes apoptosis after TNF-α/cycloheximide treatment.\",\n \"method\": \"siRNA knockdown, overexpression, western blot for kinase phosphorylation, cell migration assays, apoptosis assays\",\n \"journal\": \"Cellular signalling\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with kinase phosphorylation readouts; single lab, multiple orthogonal functional assays\",\n \"pmids\": [\"29729335\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"In Physcomitrella patens, exocyst subunit Sec6 (but not Sec3 or Sec5) localizes to microtubule overlap regions in the phragmoplast prior to cell plate membrane arrival. Sec6 physically interacts with KEULE (a Sec1/Munc18 ortholog). Sec6 gene silencing delays recruitment of KEULE and vesicles to the early cell plate, indicating Sec6 promotes vesicle-vesicle fusion at microtubule overlaps independently of vesicle delivery.\",\n \"method\": \"Live-cell fluorescence microscopy, co-immunoprecipitation, gene silencing, time-lapse imaging\",\n \"journal\": \"Journal of cell science\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — live imaging localization with functional gene silencing plus co-IP; plant ortholog study, single lab\",\n \"pmids\": [\"30635445\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2020,\n \"finding\": \"Tnfaip2/Exoc3 acts epistatically upstream of vimentin (Vim) in controlling lipid metabolism during stem cell differentiation; Tnfaip2 knockout impairs induction of triacylglycerol synthesis and lipid droplet formation in differentiating ESCs. Knockdown of planarian Smed-exoc3 also causes strong reduction of TAGs. Supplementation with palmitic acid rescues both ESC differentiation and planarian organ maintenance, placing Exoc3 upstream of TAG/lipid droplet biosynthesis required for differentiation.\",\n \"method\": \"Genetic knockout/knockdown, lipidomics, epistasis analysis, rescue with palmitic acid supplementation\",\n \"journal\": \"EMBO reports\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two independent model systems (mouse ESCs and planarians) with metabolic rescue; single lab\",\n \"pmids\": [\"33300287\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"EXOC3 conditional knockout in mouse megakaryocytes/platelets causes defects in platelet aggregation, integrin activation, α-granule secretion (P-selectin, PF4), dense granule secretion, and lysosomal granule secretion after GPVI agonist stimulation. GPVI surface levels were decreased 14.5% in KO platelets, with defects in proximal GPVI signaling (Syk and LAT phosphorylation) and calcium mobilization. PAR4-stimulated responses were paradoxically enhanced in KO platelets, and suppressed by P2Y12 antagonist, implicating enhanced ADP release. EXOC3 KO mice show accelerated arterial thrombosis and improved hemostasis.\",\n \"method\": \"Conditional knockout mice, platelet aggregometry, granule secretion assays, flow cytometry, phosphorylation analysis, calcium imaging, in vivo thrombosis model, tail bleeding time\",\n \"journal\": \"Blood advances\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with multiple orthogonal functional readouts including signaling, secretion, and in vivo thrombosis\",\n \"pmids\": [\"33560379\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2023,\n \"finding\": \"Two truncated forms of human Sec6 (HuSec6 121-734 and HuSec6 121-745) were expressed, purified (>95% purity), and crystallized; X-ray diffraction yielded ~9 Å resolution crystals, providing initial structural data for human Sec6.\",\n \"method\": \"Recombinant protein expression in E. coli, X-ray crystallography (9 Å resolution)\",\n \"journal\": \"Studies in health technology and informatics\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 1 / Weak — crystallography initiated but only low-resolution diffraction reported; no functional validation; single preliminary study\",\n \"pmids\": [\"38007759\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"Male germ cell-specific conditional knockout of Exoc3 (SEC6) in mice does not cause spermatogenesis defects, establishing that EXOC3 is not required for spermatogenesis (negative finding).\",\n \"method\": \"Conditional knockout mice, histological analysis of spermatogenesis\",\n \"journal\": \"Experimental animals\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined negative phenotypic readout; single study\",\n \"pmids\": [\"38325858\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"Sec6 suppresses innate immune responses to bovine herpesvirus 1 (BoHV-1) by promoting NDP52-mediated autophagic degradation of STING. Mechanistically, Sec6 enhances the physical interaction between NDP52 and STING; NDP52 knockdown abolishes Sec6-mediated IFN-β suppression and Sec6's ability to enhance viral replication.\",\n \"method\": \"Overexpression/knockdown, co-immunoprecipitation, autophagic flux assays, IFN-β reporter assay, viral replication assay\",\n \"journal\": \"Veterinary microbiology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interaction plus epistasis (NDP52 KD rescues phenotype); single lab, bovine cell model\",\n \"pmids\": [\"41406560\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"Sec6 suppresses BEFV-triggered type I IFN signaling by promoting P62-mediated autophagic degradation of MAVS. Sec6 enhances the P62-MAVS interaction; P62 knockdown abolishes Sec6-mediated IFN-I suppression and viral replication enhancement. Sec6 fails to degrade MAVS in P62-knockdown cells.\",\n \"method\": \"Overexpression/knockdown, co-immunoprecipitation, autophagic flux assays, IFN-I reporter assay, viral replication assay\",\n \"journal\": \"Veterinary microbiology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus epistasis (P62 KD); single lab, bovine cell model\",\n \"pmids\": [\"40780029\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"EXOC3/Sec6 is a core subunit of the octameric exocyst tethering complex that physically associates with other exocyst subunits (Sec8, Sec15, etc.) and directly binds SNARE proteins (Sec9/Sso1 complexes) and the SM protein Sec1/Munc18 to coordinate secretory vesicle tethering and SNARE-mediated fusion at the plasma membrane; in polarized epithelial cells it is recruited to cell-cell contact sites via E-cadherin and nectin adhesion complexes to direct basolateral exocytic traffic, in neurons it localizes to presynaptic membranes, and in platelets it is required for granule secretion and GPVI signaling; it also engages RalA GTPase signaling (via competitive Sec5/Exo84 effector binding), modulates p38 MAPK-MK2-HSP27 and NF-κB/IκBα signaling cascades, controls lipid metabolism upstream of vimentin during stem cell differentiation, and can promote autophagic degradation of innate immune adaptors STING and MAVS.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"EXOC3/Sec6 is a core subunit of the octameric exocyst, a multisubunit tethering complex that directs secretory vesicle delivery and fusion at the plasma membrane [#0, #1]. First defined in budding yeast as a soluble ~85 kDa protein required for fusion of post-Golgi vesicles, Sec6 is a stable component of the ~1–2 MDa Sec6/8/15 complex that localizes to sites of active exocytosis [#0, #1]. In mammalian cells the complex cycles between a cytosolic pool and membrane-recruited states, residing on both the trans-Golgi network and plasma membrane and being required for multiple steps of TGN-to-plasma-membrane exocytic transport [#4]. In polarized epithelia, calcium-dependent cell-cell adhesion recruits the complex to lateral contacts in association with E-cadherin and nectin-2α and tight junction proteins, a localization sufficient to direct basolateral surface biogenesis [#2, #8]. Mechanistically, Sec6 couples tethering to SNARE-mediated fusion: it directly and mutually exclusively binds the plasma membrane SNARE Sec9 and the Sec1/Munc18 SM protein Sec1, binds binary and ternary Sso1-Sec9-Snc2 SNARE complexes, and engages the exocyst itself in a manner incompatible with Sec9 binding, supporting a sequential hand-off model upon vesicle arrival [#13, #14]. The complex is regulated by the small GTPase RalA, which binds the Sec5 and Exo84 subunits competitively through overlapping switch-region interfaces to control complex assembly [#7, #9]. Beyond canonical secretion, EXOC3 supports developmental and physiological trafficking demonstrated genetically across systems: it acts as a Rab11-recycling-endosome effector for apical and adherens-junction cargo delivery in Drosophila [#10, #11], is required for platelet granule secretion, integrin activation and GPVI signaling with consequences for thrombosis and hemostasis [#22], and acts upstream of vimentin to control triacylglycerol/lipid-droplet biosynthesis during stem cell differentiation [#21]. EXOC3 also negatively regulates innate antiviral immunity by promoting selective-autophagy receptor–mediated degradation of the adaptors STING (via NDP52) and MAVS (via P62) [#25, #26].\",\n \"teleology\": [\n {\n \"year\": 1992,\n \"claim\": \"Established that Sec6 is a discrete gene product essential for the terminal step of secretion, answering whether post-Golgi vesicle fusion at the plasma membrane requires a dedicated soluble factor.\",\n \"evidence\": \"Gene cloning by complementation, fractionation, and synthetic lethality with sec8 in S. cerevisiae\",\n \"pmids\": [\"1523887\"],\n \"confidence\": \"High\",\n \"gaps\": [\"No biochemical complex defined\", \"No molecular partners or mechanism of action identified\"]\n },\n {\n \"year\": 1995,\n \"claim\": \"Defined Sec6 as a stable subunit of a large multiprotein assembly localized to exocytic sites, transforming it from an isolated gene into a complex component.\",\n \"evidence\": \"Affinity chromatography, gel filtration, sucrose gradients, co-IP, and immunofluorescence in yeast\",\n \"pmids\": [\"7615633\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Subunit stoichiometry and architecture unresolved\", \"Direct molecular activity of Sec6 within the complex unknown\"]\n },\n {\n \"year\": 2000,\n \"claim\": \"Extended exocyst function to mammalian polarized trafficking and signaling-organelle scaffolding, showing the complex is recruited to membrane domains and links to adhesion and Ca2+ machinery.\",\n \"evidence\": \"Permeabilized-cell antibody inhibition with cargo readouts in MDCK cells; reciprocal co-IP and Ca2+ assays in pancreatic acinar cells\",\n \"pmids\": [\"9630218\", \"10973998\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Which subunit mediates membrane recruitment not resolved\", \"Ca2+-protein associations are correlative, mechanism indirect\"]\n },\n {\n \"year\": 2001,\n \"claim\": \"Mapped exocyst itinerary and intra-complex interactions, showing the complex functions at both TGN and plasma membrane steps of exocytosis.\",\n \"evidence\": \"Semiintact-cell antibody inhibition with pharmacology in NRK cells; yeast two-hybrid mapping of human subunit contacts\",\n \"pmids\": [\"11696560\", \"11493706\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Sec6-specific contribution to each step not isolated\", \"GFP-subunit assembly failures leave human complex architecture unclear\"]\n },\n {\n \"year\": 2004,\n \"claim\": \"Identified the molecular cue specifying exocyst localization in epithelia, answering how the complex finds lateral membrane domains.\",\n \"evidence\": \"Co-IP with surface-labeled E-cadherin/nectin-2α and reconstitution in fibroblasts (MDCK system)\",\n \"pmids\": [\"14709721\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direct vs indirect binding to cadherin/nectin not distinguished\", \"Subunit responsible for adhesion-complex contact unknown\"]\n },\n {\n \"year\": 2005,\n \"claim\": \"Provided structural and genetic mechanism for GTPase regulation and developmental cargo trafficking, establishing RalA as a competitive regulator and the exocyst as a Rab11 effector.\",\n \"evidence\": \"Crystallography of Exo84-RalA with competition assays; Drosophila sec6 loss-of-function with cargo trafficking phenotypes and co-IP\",\n \"pmids\": [\"15920473\", \"15897260\", \"16224820\"],\n \"confidence\": \"High\",\n \"gaps\": [\"RalA regulation maps to Sec5/Exo84, not Sec6 directly\", \"How Rab11 endosome trafficking integrates with SNARE fusion unresolved\"]\n },\n {\n \"year\": 2015,\n \"claim\": \"Resolved how Sec6 couples tethering to fusion machinery, showing direct, mutually exclusive binding to SNARE and SM proteins that orders assembly events.\",\n \"evidence\": \"In vitro binding/SNARE-assembly kinetics, cross-linking MS, and mutagenesis with yeast growth validation\",\n \"pmids\": [\"22114349\", \"26446795\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Sequential hand-off model not directly visualized on vesicles\", \"Conservation of Sec6-SM/SNARE coupling in mammals not demonstrated\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Demonstrated a vesicle-vesicle fusion role at cytoskeletal sites independent of delivery, broadening Sec6 function beyond plasma-membrane tethering.\",\n \"evidence\": \"Live imaging, gene silencing, and co-IP with KEULE in Physcomitrella patens phragmoplast\",\n \"pmids\": [\"30635445\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Plant-ortholog finding; mammalian relevance untested\", \"Mechanism of microtubule-overlap targeting unknown\"]\n },\n {\n \"year\": 2021,\n \"claim\": \"Established a physiological secretory requirement in mammals in vivo, showing EXOC3 is essential for platelet granule secretion and receptor signaling with thrombotic consequences.\",\n \"evidence\": \"Conditional knockout mice with aggregometry, secretion assays, signaling readouts, and in vivo thrombosis/bleeding models\",\n \"pmids\": [\"33560379\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Whether defects reflect canonical exocyst tethering or additional roles not dissected\", \"Mechanism of paradoxical PAR4 enhancement only partially explained\"]\n },\n {\n \"year\": 2020,\n \"claim\": \"Linked EXOC3 to lipid metabolism in differentiation, placing it upstream of vimentin in controlling TAG/lipid-droplet biosynthesis.\",\n \"evidence\": \"Genetic knockout/knockdown, lipidomics, epistasis, and palmitic acid rescue in mouse ESCs and planarians\",\n \"pmids\": [\"33300287\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Molecular link between exocyst tethering and lipid synthesis not defined\", \"Whether function requires exocyst complex unknown\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Identified a function in innate immune suppression, showing EXOC3 promotes selective autophagic degradation of antiviral adaptors.\",\n \"evidence\": \"Overexpression/knockdown, co-IP, autophagic flux, IFN reporters, and viral replication assays with NDP52/P62 epistasis in bovine cells\",\n \"pmids\": [\"41406560\", \"40780029\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Single-lab, bovine cell models\", \"Whether degradation requires the intact exocyst complex untested\", \"Direct vs scaffold role in receptor-adaptor recruitment unresolved\"]\n },\n {\n \"year\": null,\n \"claim\": \"How EXOC3 mechanistically bridges its canonical exocyst tethering/SNARE-coupling activity with the diverse signaling, metabolic, and autophagy phenotypes attributed to it in mammalian systems remains unresolved.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"Medium\",\n \"gaps\": [\"No high-resolution structure of human Sec6 or the assembled human exocyst\", \"Whether non-secretory roles depend on the intact complex untested\", \"Direct binding partners for mammalian signaling/autophagy functions not biochemically defined\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 14]},\n {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 4]},\n {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 8]},\n {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 4]},\n {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 4]}\n ],\n \"complexes\": [\"exocyst (Sec6/8/15 complex)\"],\n \"partners\": [\"EXOC4\", \"EXOC6\", \"Sec9\", \"Sec1\", \"RALA\", \"CDH1\", \"RAB11\", \"NDP52\"],\n \"other_free_text\": []\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}