{"gene":"EXOC4","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"Sec8p (EXOC4) is a component of a 19.5S particle that also contains Sec15p; this particle is found in the cytosol and peripherally associated with the plasma membrane (not with secretory vesicles), and a portion of Sec4p (Rab GTPase) co-fractionates with it, suggesting the complex functions as a downstream effector of Sec4p to direct vesicle fusion with the plasma membrane.","method":"Subcellular fractionation, sucrose gradient sedimentation, gel filtration, cross-linking, co-fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (fractionation, sedimentation, gel filtration) in a foundational study replicated by subsequent work","pmids":["1512289"],"is_preprint":false},{"year":1995,"finding":"Sec8 (EXOC4) is a stable component of a multisubunit (~1-2 MDa) complex (the exocyst) containing at least Sec3, Sec5, Sec6, Sec10, Sec15, and additional polypeptides; the integrity of this complex depends on Sec3, Sec5, and Sec10; the complex localizes to small bud tips in S. cerevisiae, consistent with a role at sites of exocytosis.","method":"Immobilized metal affinity chromatography (His-tag), immunoprecipitation with c-myc-tagged Sec8, gel filtration, sucrose velocity sedimentation, immunofluorescence localization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and imaging methods, foundational study replicated widely","pmids":["7615633"],"is_preprint":false},{"year":1997,"finding":"The mouse sec8 gene is required for paraxial mesoderm formation; homozygous sec8 mutant embryos initiate gastrulation but cannot progress beyond the primitive streak stage, establishing an essential in vivo developmental role for Sec8 (EXOC4).","method":"Gene trap screen in embryonic stem cells, homozygous mutant mouse analysis, cDNA cloning and sequencing","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with a defined developmental phenotype in mouse","pmids":["9441674"],"is_preprint":false},{"year":2003,"finding":"Sec8 (EXOC4) binds to PDZ1 and PDZ2 domains of PSD-95 via its C-terminal Thr-Thr-Val (TTV) motif; this interaction can be competed by PDZ-binding peptides and is blocked by deletion of the TTV sequence. Cypin (cytosolic PSD-95 interactor) competes with Sec8 for binding to PSD-95, suggesting cypin negatively regulates Sec8–PSD-95 complex formation.","method":"Co-immunoprecipitation from brain tissue, peptide competition assay, immunoblotting of subcellular fractions, deletion/mutation analysis of the C-terminal TTV motif","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus competition assay, single lab, two orthogonal approaches","pmids":["12675619"],"is_preprint":false},{"year":2005,"finding":"In Drosophila, Sec8 is required in vivo for regulation of synaptic microtubule density (approximately doubled in sec8 null mutants) and influences synaptic growth and glutamate receptor trafficking at the neuromuscular junction; no requirement for basal neurotransmission was detected.","method":"Forward genetic screen, generation of sec8 null mutants, immunocytochemistry with anti-Sec8 antibodies, synaptic electrophysiology, immunoblotting for maternal contribution","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null mutant with multiple phenotypic readouts (morphology, electrophysiology), single study","pmids":["16351720"],"is_preprint":false},{"year":2006,"finding":"Sec8 (EXOC4) colocalizes, co-immunoprecipitates, and co-fractionates with the myelin protein OSP/Claudin11 and with the scaffolding protein CASK in oligodendrocytes. Sec8 overexpression promotes oligodendrocyte morphological differentiation and myelin-like membrane formation in vitro, whereas siRNA-mediated Sec8 knockdown inhibits this process, placing Sec8 as a central regulator of vesicle recruitment to sites of myelin membrane growth.","method":"Co-immunoprecipitation, co-fractionation, immunofluorescence colocalization, Sec8 overexpression and siRNA knockdown with morphological/differentiation readouts, anti-Sec8 antibody perturbation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional gain/loss-of-function, single lab","pmids":["16478790"],"is_preprint":false},{"year":2009,"finding":"In Schwann cells, Sec8 (EXOC4) interacts with Dlg1 (Discs large 1); this interaction promotes membrane addition during myelination. In the Mtmr2-null model of myelin outfoldings, the Dlg1–Sec8 interaction contributes to excess membrane formation, while Dlg1–Mtmr2 interaction negatively regulates membrane formation.","method":"Co-immunoprecipitation in Schwann cells, Mtmr2-null mouse model, Schwann cell/DRG coculture with Mtmr2 rescue, immunofluorescence localization","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic model with functional rescue, single lab","pmids":["19587293"],"is_preprint":false},{"year":2009,"finding":"Insulin stimulates phosphorylation of Sec8 (EXOC4) at Ser-32 in 3T3-L1 adipocytes via a PI3K-dependent pathway (likely Akt); however, overexpression of non-phosphorylatable S32A or phosphomimetic S32E Sec8 mutants had no detectable effect on insulin-stimulated GLUT4 or transferrin receptor trafficking to the plasma membrane.","method":"Phosphoproteomics (mass spectrometry), pharmacological inhibition (wortmannin), overexpression of phosphorylation-site mutants (S32A, S32E), surface GLUT4/TfR assay","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in-cell phosphorylation identified by MS plus mutagenesis, but functional effect on GLUT4 was explicitly negative; negative result recorded accordingly","pmids":["19006485"],"is_preprint":false},{"year":2010,"finding":"In Schizosaccharomyces pombe, Sec8p is required for mating-specific cell adhesion, and both Sec8p and Exo70p are required for proper spore cell wall development, demonstrating distinct roles for different exocyst subunits in sexual development.","method":"sec8-1 temperature-sensitive mutant and exo70Δ null analysis, immunofluorescence (Meu14p localization), genetic epistasis/complementation","journal":"FEMS microbiology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetics with specific phenotypic readouts, single lab fission yeast study","pmids":["20180855"],"is_preprint":false},{"year":2012,"finding":"Sec8 (EXOC4) knockdown in oral squamous cell carcinoma cells reduces cellular invasion and secretion of matrix metalloproteinases MMP-2 and MMP-9 (by gelatin zymography), consistent with a role for Sec8 in tethering MMP-containing secretory vesicles to the plasma membrane.","method":"siRNA knockdown, invasion assay, gelatin zymography for MMP secretion, proliferation assay","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single siRNA knockdown approach with phenotypic readouts but no direct pathway dissection","pmids":["23207790"],"is_preprint":false},{"year":2014,"finding":"Sec8 (EXOC4) knockdown promotes G1/S cell cycle arrest by increasing p21(Cip1) expression via stabilization of FOXO transcription factors; Sec8 normally promotes FOXO ubiquitin-proteasome degradation through regulation of Mdm2 (but not Skp2), and its loss also reduces retinoblastoma protein phosphorylation.","method":"siRNA knockdown, cell cycle analysis (flow cytometry), immunoblotting for p21/FOXO/Mdm2/Skp2/pRb, proteasome inhibitor experiments","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown plus western blotting, no direct biochemical reconstitution","pmids":["24299491"],"is_preprint":false},{"year":2014,"finding":"Sec8 (EXOC4) binds JIP4 (JNK-interacting protein 4); Sec8 knockdown enhances JIP4 binding to MKK4, resulting in decreased phosphorylation of MKK4, JNK, and p38 MAPK, thereby suppressing apoptosis.","method":"Co-immunoprecipitation, siRNA knockdown, phosphorylation assays (western blot for pMKK4, pJNK, pp38), apoptosis assays","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP plus knockdown, single lab, no in vitro reconstitution","pmids":["25244576"],"is_preprint":false},{"year":2015,"finding":"Sec8 (EXOC4) knockdown suppresses cell migration by reducing phosphorylation of cytokeratin8 at Ser73; this is mediated through activation of ERK and p38 MAPK signaling pathways via downregulation of PAK (p21-activated kinase) activity, itself regulated by Pirh2 and Siah1 E3 ligases.","method":"siRNA knockdown, migration assay, phospho-specific immunoblotting for CK8-pSer73 and MAPK pathway components, rescue experiments","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with western blot readouts, indirect pathway placement","pmids":["25725287"],"is_preprint":false},{"year":2016,"finding":"Sec8 (EXOC4) knockdown decreases Smad3 and Smad4 expression at the basal transcriptional level (dependent on CBP/CREB-binding protein), thereby reducing N-cadherin expression and modulating TGF-β-induced epithelial-mesenchymal transition and cell migration/adhesion.","method":"siRNA knockdown of Sec8 and CBP, RT-PCR and immunoblotting for N-cadherin, Smad3, Smad4, CBP; cell migration and adhesion assays","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown plus western blot, no direct biochemical interaction demonstrated","pmids":["27769780"],"is_preprint":false},{"year":2016,"finding":"CREG1 directly interacts with Sec8 (EXOC4) of the exocyst complex; this interaction is required for cardiomyocyte differentiation and cell cohesion. CREG1, Sec8, and N-cadherin colocalize at intercalated discs in vivo and at cell-cell junctions in cultured cardiomyocytes. CREG1 knockout disrupts the Sec8–N-cadherin interaction and induces their degradation, while CREG1 overexpression enhances adherens and gap junction assembly.","method":"Co-immunoprecipitation, site-directed mutagenesis of CREG1, rescue of CREG1 KO ES cells, immunofluorescence colocalization, gain/loss-of-function differentiation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis-based rescue, single lab with multiple orthogonal methods","pmids":["27334848"],"is_preprint":false},{"year":2021,"finding":"LRRK2 interacts with Sec8 (EXOC4); LRRK2 kinase activity and presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits, and overexpression of Sec8 significantly rescues the pathological effects of the LRRK2 G2019S Parkinson's disease mutation.","method":"Co-immunoprecipitation, overexpression of Sec8 in LRRK2 G2019S cells, exocyst subunit co-assembly assays, rescue phenotype analysis","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP plus overexpression rescue, no in vitro reconstitution","pmids":["33498474"],"is_preprint":false},{"year":2022,"finding":"EXOC4 (Sec8) promotes diffuse-type gastric cancer cell migration/invasion and tumor metastasis by stimulating secretion of integrin α5/β1 and EGF, enhancing integrin/EGFR–FAK interaction, and increasing phosphorylation of FAK at Y397; the FAK inhibitor VS-4718 reverses EXOC4-driven metastasis.","method":"LC-MS/MS proteomics identification, siRNA knockdown and overexpression, migration/invasion assays, phospho-FAK immunoblotting, co-immunoprecipitation (FAK–integrin/EGFR), xenograft and patient-derived xenograft models, pharmacological FAK inhibition","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, phosphoblotting, in vivo PDX, pharmacological rescue), single lab","pmids":["35471457"],"is_preprint":false},{"year":2023,"finding":"Crystal structure (2.5 Å) of the C-terminal half of Sec8 (EXOC4) containing the ITTV PDZ-binding motif reveals an unusually long C-terminal helix with a 14-residue 'spacer' bridging the ITTV motif to the compact Sec8 core. Sec8 preferentially binds PDZ2 over PDZ1 and PDZ3 of SAP102; deletion of the spacer completely abolishes binding to SAP102.","method":"X-ray crystallography (2.5 Å resolution), in vitro binding assays, deletion mutagenesis of the spacer region, computational modeling","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis and binding assays, single lab but orthogonal methods","pmids":["37849738"],"is_preprint":false},{"year":2025,"finding":"EXOC4 (Sec8) stabilizes STING1 by suppressing K27-linked ubiquitination at STING1 residues K338, K347, and K370 catalyzed by the E3 ligase FBXL19, thereby preventing SQSTM1-mediated autophagic degradation of STING1 and promoting type I interferon signaling in response to DNA viruses. Conditional Exoc4/Sec8 knockout mice show increased susceptibility to HSV-1 infection.","method":"Co-immunoprecipitation, ubiquitination site mapping/mutagenesis, EXOC4 knockdown/overexpression, IFN reporter assays, antiviral replication assays, conditional knockout mouse model, microscale thermophoresis (MST) for binding","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, mutagenesis, MST, KO mouse), single lab","pmids":["40413753"],"is_preprint":false},{"year":2026,"finding":"Sec8 (EXOC4) stabilizes RIG-I by competing with the E3 ligase STUB1 for binding to RIG-I's CARD domain, thereby inhibiting STUB1-mediated K48-linked ubiquitination of RIG-I at Lys190 and its proteasomal degradation. Additionally, Sec8 reduces STUB1 mRNA by suppressing p53 expression. Sec8-deficient mice show increased susceptibility to RNA virus infection.","method":"Co-immunoprecipitation (Sec8–RIG-I, STUB1–RIG-I), ubiquitination assays with site-specific mutants (RIG-I K190), Sec8 KO mice, in vivo and in vitro antiviral assays, p53/STUB1 expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ubiquitination site mutagenesis, in vivo KO mouse, single lab multiple methods","pmids":["41580425"],"is_preprint":false},{"year":2026,"finding":"p300-mediated acetylation of EXOC4 at lysine 433 induces its nuclear translocation. In the nucleus, EXOC4 facilitates the interaction between PRMT5 and KU70, enabling PRMT5-catalyzed methylation of KU70 at arginine 318, which increases KU complex DNA-binding affinity and accelerates double-strand break repair by non-homologous end joining (NHEJ), thereby promoting chemoradiotherapy resistance in gastric cancer.","method":"Site-directed mutagenesis (K433), nuclear fractionation, co-immunoprecipitation (EXOC4–PRMT5–KU70), PRMT5 methylation assay, DNA-binding affinity assay, inhibitory peptide targeting K433, preclinical xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus co-IP plus in vivo preclinical models, single lab, multiple orthogonal approaches","pmids":["41826730"],"is_preprint":false}],"current_model":"EXOC4/Sec8 is a core subunit of the evolutionarily conserved ~1–2 MDa exocyst complex that tethers secretory vesicles to specific plasma membrane docking sites; beyond this canonical vesicle-tethering role (supported by yeast biochemistry and structural studies), EXOC4 regulates synaptic microtubule density and myelination, binds synaptic scaffold proteins PSD-95 and SAP102 via its C-terminal ITTV/TTV PDZ-binding motif (structurally characterized at 2.5 Å), controls cell cycle progression and migration through FOXO/p21 and MAPK pathways, promotes antiviral innate immunity by stabilizing both STING1 (against DNA viruses, via suppression of FBXL19-mediated K27-ubiquitination) and RIG-I (against RNA viruses, via competition with STUB1-mediated K48-ubiquitination), and—in a non-canonical nuclear role—undergoes p300-acetylation at K433 to translocate to the nucleus where it facilitates PRMT5-mediated KU70 methylation and NHEJ-dependent DNA repair."},"narrative":{"mechanistic_narrative":"EXOC4/Sec8 is a core subunit of the conserved ~1–2 MDa exocyst complex that tethers secretory vesicles to plasma membrane docking sites and acts downstream of the Rab GTPase Sec4 to direct vesicle fusion [PMID:1512289, PMID:7615633]. This tethering function underlies essential physiological roles, including paraxial mesoderm formation during mouse gastrulation [PMID:9441674] and, in fungal systems, mating-specific cell adhesion and spore cell wall development [PMID:20180855]. In neural tissue, Sec8 regulates synaptic microtubule density, synaptic growth, and glutamate receptor trafficking [PMID:16351720], and engages synaptic scaffold proteins of the PSD-95/SAP102 (MAGUK) family through a C-terminal TTV/ITTV PDZ-binding motif; structural analysis shows that an unusually long C-terminal helix with a 14-residue spacer bridges the ITTV motif to the Sec8 core and confers preferential binding to the PDZ2 domain of SAP102 [PMID:12675619, PMID:37849738]. Through interactions with scaffolds such as CASK and Dlg1, Sec8 directs vesicle recruitment to sites of myelin membrane growth in oligodendrocytes and Schwann cells [PMID:16478790, PMID:19587293], and its binding to CREG1 stabilizes a Sec8–N-cadherin axis required for cardiomyocyte differentiation and cell-cell junction assembly [PMID:27334848]. EXOC4 also promotes tumor cell migration and invasion by enhancing secretion of integrin α5β1 and EGF and driving integrin/EGFR–FAK signaling [PMID:35471457]. Beyond vesicle tethering, EXOC4 stabilizes antiviral sensors: it suppresses FBXL19-mediated K27-linked ubiquitination of STING1 to block its autophagic degradation and sustain type I interferon responses to DNA viruses [PMID:40413753], and competes with STUB1 for the RIG-I CARD domain to inhibit K48-linked ubiquitination and degradation of RIG-I against RNA viruses [PMID:41580425]. In a non-canonical nuclear role, p300-mediated acetylation of EXOC4 at K433 drives nuclear translocation, where EXOC4 bridges PRMT5 and KU70 to enable arginine methylation of KU70 and enhance NHEJ-dependent double-strand break repair [PMID:41826730].","teleology":[{"year":1992,"claim":"Established that Sec8 is not a free protein but part of a discrete particle acting downstream of a Rab GTPase, framing it as an effector that targets vesicle fusion to the plasma membrane.","evidence":"Subcellular fractionation, sucrose gradient sedimentation, gel filtration and cross-linking with Sec4 co-fractionation in yeast","pmids":["1512289"],"confidence":"High","gaps":["Did not resolve full subunit composition","Mechanism of Sec4-dependent activation not defined"]},{"year":1995,"claim":"Defined Sec8 as a stable subunit of a multisubunit ~1–2 MDa complex (the exocyst) localized to sites of active exocytosis, establishing the molecular machine in which EXOC4 operates.","evidence":"His-tag affinity chromatography, co-IP of tagged Sec8, gel filtration, sedimentation, and immunofluorescence in S. cerevisiae","pmids":["7615633"],"confidence":"High","gaps":["Subunit stoichiometry and architecture not resolved","No structural model of intact complex"]},{"year":1997,"claim":"Demonstrated an essential in vivo developmental requirement for Sec8, moving it beyond a yeast housekeeping factor to a metazoan morphogenetic regulator.","evidence":"Gene-trap loss-of-function in mouse embryos with gastrulation phenotype analysis","pmids":["9441674"],"confidence":"High","gaps":["Cell-type-specific secretory cargo driving the phenotype unknown","Did not separate exocyst-dependent from independent roles"]},{"year":2003,"claim":"Identified the C-terminal TTV motif as a PDZ-binding module linking Sec8 to the postsynaptic scaffold PSD-95, providing a mechanism for targeting the exocyst to synaptic sites.","evidence":"Brain co-IP, peptide competition, and C-terminal motif deletion/mutation","pmids":["12675619"],"confidence":"Medium","gaps":["Functional consequence of synaptic targeting not tested in vivo","Single-lab biochemistry"]},{"year":2005,"claim":"Showed Sec8 controls synaptic microtubule density and receptor trafficking, distinguishing a structural/cargo-targeting role from basal neurotransmission.","evidence":"Drosophila sec8 null mutants with immunocytochemistry, electrophysiology, and morphological readouts","pmids":["16351720"],"confidence":"Medium","gaps":["Molecular link between exocyst and microtubule regulation unresolved","Mammalian conservation not shown"]},{"year":2006,"claim":"Placed Sec8 as a regulator of vesicle recruitment to growing myelin membrane via interactions with CASK and OSP/Claudin11.","evidence":"Co-IP, co-fractionation, colocalization, and gain/loss-of-function in oligodendrocytes","pmids":["16478790"],"confidence":"Medium","gaps":["Direct vs indirect Claudin11 interaction not dissected","In vivo myelination requirement not tested here"]},{"year":2009,"claim":"Extended the myelination role to Schwann cells through a Dlg1–Sec8 axis that drives membrane addition, linked to a disease model of myelin outfoldings.","evidence":"Co-IP in Schwann cells plus Mtmr2-null mouse model with coculture rescue","pmids":["19587293"],"confidence":"Medium","gaps":["Quantitative contribution of Sec8 to membrane excess not isolated","Direct binding interface undefined"]},{"year":2009,"claim":"Tested whether insulin/PI3K signaling regulates Sec8 to control GLUT4 trafficking; identified a phosphosite but found no functional effect, constraining models of insulin-regulated exocytosis.","evidence":"Phosphoproteomics, wortmannin inhibition, and S32A/S32E mutant overexpression in adipocytes","pmids":["19006485"],"confidence":"Medium","gaps":["Functional role of Ser32 phosphorylation unknown (negative result)","Other regulatory sites not examined"]},{"year":2010,"claim":"Showed subunit-specific exocyst functions in fungal sexual development, indicating EXOC4 contributes non-redundant roles distinct from other subunits.","evidence":"sec8-1 ts and exo70Δ mutants with localization and genetic epistasis in S. pombe","pmids":["20180855"],"confidence":"Medium","gaps":["Molecular basis of subunit specialization unknown","Relevance to metazoan EXOC4 unclear"]},{"year":2016,"claim":"Identified a direct CREG1–Sec8 interaction stabilizing a Sec8–N-cadherin complex required for cardiomyocyte differentiation and junction assembly.","evidence":"Reciprocal co-IP, CREG1 mutagenesis/rescue in ES cells, colocalization, and differentiation assays","pmids":["27334848"],"confidence":"Medium","gaps":["Whether N-cadherin is an exocyst cargo or stable partner unresolved","Mechanism of CREG1-dependent stabilization undefined"]},{"year":2022,"claim":"Defined a pro-metastatic secretory program in which EXOC4 drives integrin/EGF secretion and FAK activation, with pharmacological FAK inhibition reversing the phenotype.","evidence":"LC-MS/MS, knockdown/overexpression, phospho-FAK blotting, co-IP, PDX models, and FAK inhibitor rescue in gastric cancer","pmids":["35471457"],"confidence":"Medium","gaps":["Whether effect is purely exocyst tethering vs additional signaling unclear","Direct EXOC4 cargo selectivity not defined"]},{"year":2023,"claim":"Provided structural mechanism for Sec8–MAGUK targeting, showing a long C-terminal helix and spacer required for selective binding to SAP102 PDZ2.","evidence":"2.5 Å crystal structure, in vitro binding, and spacer deletion mutagenesis","pmids":["37849738"],"confidence":"High","gaps":["Functional role of PDZ2 selectivity in neurons not tested","Structure limited to C-terminal half"]},{"year":2025,"claim":"Revealed a non-canonical innate-immune function: EXOC4 stabilizes STING1 against FBXL19-mediated K27 ubiquitination and autophagic degradation to sustain anti-DNA-virus interferon responses.","evidence":"Co-IP, ubiquitination site mapping, MST binding, IFN/antiviral assays, and conditional KO mice challenged with HSV-1","pmids":["40413753"],"confidence":"Medium","gaps":["Whether stabilization requires intact exocyst unknown","Mechanism of competition with FBXL19 not structurally defined"]},{"year":2026,"claim":"Extended antiviral function to RNA virus sensing by showing EXOC4 protects RIG-I from STUB1-mediated K48 ubiquitination and degradation, partly via p53/STUB1 suppression.","evidence":"Reciprocal co-IP, RIG-I K190 ubiquitination mutants, p53/STUB1 analysis, and KO mice in antiviral assays","pmids":["41580425"],"confidence":"Medium","gaps":["Direct competition interface with STUB1 not structurally resolved","Link between exocyst tethering role and immune stabilization unclear"]},{"year":2026,"claim":"Established a nuclear, repair-promoting role for EXOC4 in which K433 acetylation drives translocation and EXOC4 bridges PRMT5–KU70 to enhance NHEJ and therapy resistance.","evidence":"K433 mutagenesis, nuclear fractionation, co-IP, PRMT5 methylation and DNA-binding assays, inhibitory peptide, and xenografts","pmids":["41826730"],"confidence":"Medium","gaps":["How a cytoplasmic exocyst subunit acquires DNA-repair scaffolding function unexplained","Generality beyond gastric cancer untested"]},{"year":null,"claim":"How EXOC4 partitions between its canonical exocyst tethering role and its emerging non-canonical functions in innate immunity and nuclear DNA repair, and what determines this functional switching, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking exocyst, immune, and nuclear roles","Regulatory switch (acetylation, complex assembly) controlling localization undefined","Human structural model of intact exocyst absent from this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,14,17,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,14]}],"complexes":["exocyst"],"partners":["PSD-95","SAP102","CASK","DLG1","CREG1","STING1","RIG-I","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96A65","full_name":"Exocyst complex component 4","aliases":["Exocyst complex component Sec8"],"length_aa":974,"mass_kda":110.5,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane","subcellular_location":"Midbody, Midbody ring; Cell projection; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q96A65/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC4","classification":"Common Essential","n_dependent_lines":465,"n_total_lines":1208,"dependency_fraction":0.3849337748344371},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SLC7A6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EXOC4","total_profiled":1310},"omim":[{"mim_id":"621438","title":"GLUTAMATE RECEPTOR-INTERACTING PROTEIN 2; GRIP2","url":"https://www.omim.org/entry/621438"},{"mim_id":"617368","title":"SH3 DOMAIN-BINDING PROTEIN 1; SH3BP1","url":"https://www.omim.org/entry/617368"},{"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":"608185","title":"EXOCYST COMPLEX COMPONENT 4; EXOC4","url":"https://www.omim.org/entry/608185"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOC4"},"hgnc":{"alias_symbol":["KIAA1699","MGC27170","SEC8","Sec8p"],"prev_symbol":["SEC8L1"]},"alphafold":{"accession":"Q96A65","domains":[{"cath_id":"-","chopping":"40-122","consensus_level":"medium","plddt":83.5055,"start":40,"end":122},{"cath_id":"-","chopping":"570-662_671-734_750-904","consensus_level":"medium","plddt":90.0507,"start":570,"end":904}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A65","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A65-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96A65-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOC4","jax_strain_url":"https://www.jax.org/strain/search?query=EXOC4"},"sequence":{"accession":"Q96A65","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96A65.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96A65/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96A65"}},"corpus_meta":[{"pmid":"7615633","id":"PMC_7615633","title":"Sec6, Sec8, and Sec15 are components of a multisubunit complex which localizes to small bud tips in Saccharomyces cerevisiae.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7615633","citation_count":258,"is_preprint":false},{"pmid":"1512289","id":"PMC_1512289","title":"Sec8p and Sec15p are components of a plasma membrane-associated 19.5S particle that may function downstream of Sec4p to control exocytosis.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1512289","citation_count":96,"is_preprint":false},{"pmid":"19587293","id":"PMC_19587293","title":"Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19587293","citation_count":90,"is_preprint":false},{"pmid":"9441674","id":"PMC_9441674","title":"The secretory protein Sec8 is required for paraxial mesoderm formation in the mouse.","date":"1997","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9441674","citation_count":67,"is_preprint":false},{"pmid":"12675619","id":"PMC_12675619","title":"Exocyst complex subunit sec8 binds to postsynaptic density protein-95 (PSD-95): a novel interaction regulated by cypin (cytosolic PSD-95 interactor).","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12675619","citation_count":34,"is_preprint":false},{"pmid":"16351720","id":"PMC_16351720","title":"Increased synaptic microtubules and altered synapse development in Drosophila sec8 mutants.","date":"2005","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/16351720","citation_count":31,"is_preprint":false},{"pmid":"27769780","id":"PMC_27769780","title":"Sec8 modulates TGF-β induced EMT by controlling N-cadherin via regulation of Smad3/4.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27769780","citation_count":29,"is_preprint":false},{"pmid":"16478790","id":"PMC_16478790","title":"A role for Sec8 in oligodendrocyte morphological differentiation.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16478790","citation_count":28,"is_preprint":false},{"pmid":"27334848","id":"PMC_27334848","title":"CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion.","date":"2016","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/27334848","citation_count":25,"is_preprint":false},{"pmid":"24299491","id":"PMC_24299491","title":"Knockdown of Sec8 promotes cell-cycle arrest at G1/S phase by inducing p21 via control of FOXO proteins.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24299491","citation_count":24,"is_preprint":false},{"pmid":"23207790","id":"PMC_23207790","title":"Exocyst complex component Sec8: a presumed component in the progression of human oral squamous-cell carcinoma by secretion of matrix metalloproteinases.","date":"2012","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23207790","citation_count":23,"is_preprint":false},{"pmid":"25725287","id":"PMC_25725287","title":"Sec8 regulates cytokeratin8 phosphorylation and cell migration by controlling the ERK and p38 MAPK signalling pathways.","date":"2015","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25725287","citation_count":20,"is_preprint":false},{"pmid":"25244576","id":"PMC_25244576","title":"Knockdown of Sec8 enhances the binding affinity of c-Jun N-terminal kinase (JNK)-interacting protein 4 for mitogen-activated protein kinase kinase 4 (MKK4) and suppresses the phosphorylation of MKK4, p38, and JNK, thereby inhibiting apoptosis.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/25244576","citation_count":20,"is_preprint":false},{"pmid":"18498660","id":"PMC_18498660","title":"Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.","date":"2008","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18498660","citation_count":16,"is_preprint":false},{"pmid":"15880602","id":"PMC_15880602","title":"Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population.","date":"2005","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15880602","citation_count":15,"is_preprint":false},{"pmid":"19006485","id":"PMC_19006485","title":"Insulin stimulates the phosphorylation of the exocyst protein Sec8 in adipocytes.","date":"2009","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/19006485","citation_count":15,"is_preprint":false},{"pmid":"36180927","id":"PMC_36180927","title":"Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study.","date":"2022","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36180927","citation_count":13,"is_preprint":false},{"pmid":"35471457","id":"PMC_35471457","title":"EXOC4 Promotes Diffuse-Type Gastric Cancer Metastasis via Activating FAK Signal.","date":"2022","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/35471457","citation_count":12,"is_preprint":false},{"pmid":"33671441","id":"PMC_33671441","title":"The Association of an SNP in the EXOC4 Gene and Reproductive Traits Suggests Its Use as a Breeding Marker in Pigs.","date":"2021","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/33671441","citation_count":9,"is_preprint":false},{"pmid":"20180855","id":"PMC_20180855","title":"Different steps of sexual development are differentially regulated by the Sec8p and Exo70p exocyst subunits.","date":"2010","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/20180855","citation_count":7,"is_preprint":false},{"pmid":"40413753","id":"PMC_40413753","title":"Unveiling EXOC4/SEC8: a key player in enhancing antiviral immunity by inhibiting the FBXL19-STING1-SQSTM1 signaling axis.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40413753","citation_count":4,"is_preprint":false},{"pmid":"37849738","id":"PMC_37849738","title":"Sec8 specifically interacts with the PDZ2 domain of synapse associated protein 102 (SAP102).","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37849738","citation_count":1,"is_preprint":false},{"pmid":"33498474","id":"PMC_33498474","title":"LRRK2 Modulates the Exocyst Complex Assembly by Interacting with Sec8.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33498474","citation_count":1,"is_preprint":false},{"pmid":"37152017","id":"PMC_37152017","title":"Case Report: Co-existence of a novel EXOC4-TRHDE gene fusion with PML-RARA in acute promyelocytic leukemia.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37152017","citation_count":1,"is_preprint":false},{"pmid":"41826730","id":"PMC_41826730","title":"Acetylation-dependent nuclear translocation of EXOC4 regulates KU70 methylation to facilitate non-homologous end joining.","date":"2026","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41826730","citation_count":0,"is_preprint":false},{"pmid":"41580425","id":"PMC_41580425","title":"Sec8: a novel positive regulator of RIG-I in anti-RNA viral defense.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41580425","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14576,"output_tokens":5658,"usd":0.064299,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14121,"output_tokens":4750,"usd":0.094677,"stage2_stop_reason":"end_turn"},"total_usd":0.158976,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"Sec8p (EXOC4) is a component of a 19.5S particle that also contains Sec15p; this particle is found in the cytosol and peripherally associated with the plasma membrane (not with secretory vesicles), and a portion of Sec4p (Rab GTPase) co-fractionates with it, suggesting the complex functions as a downstream effector of Sec4p to direct vesicle fusion with the plasma membrane.\",\n      \"method\": \"Subcellular fractionation, sucrose gradient sedimentation, gel filtration, cross-linking, co-fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (fractionation, sedimentation, gel filtration) in a foundational study replicated by subsequent work\",\n      \"pmids\": [\"1512289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sec8 (EXOC4) is a stable component of a multisubunit (~1-2 MDa) complex (the exocyst) containing at least Sec3, Sec5, Sec6, Sec10, Sec15, and additional polypeptides; the integrity of this complex depends on Sec3, Sec5, and Sec10; the complex localizes to small bud tips in S. cerevisiae, consistent with a role at sites of exocytosis.\",\n      \"method\": \"Immobilized metal affinity chromatography (His-tag), immunoprecipitation with c-myc-tagged Sec8, gel filtration, sucrose velocity sedimentation, immunofluorescence localization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and imaging methods, foundational study replicated widely\",\n      \"pmids\": [\"7615633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The mouse sec8 gene is required for paraxial mesoderm formation; homozygous sec8 mutant embryos initiate gastrulation but cannot progress beyond the primitive streak stage, establishing an essential in vivo developmental role for Sec8 (EXOC4).\",\n      \"method\": \"Gene trap screen in embryonic stem cells, homozygous mutant mouse analysis, cDNA cloning and sequencing\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with a defined developmental phenotype in mouse\",\n      \"pmids\": [\"9441674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sec8 (EXOC4) binds to PDZ1 and PDZ2 domains of PSD-95 via its C-terminal Thr-Thr-Val (TTV) motif; this interaction can be competed by PDZ-binding peptides and is blocked by deletion of the TTV sequence. Cypin (cytosolic PSD-95 interactor) competes with Sec8 for binding to PSD-95, suggesting cypin negatively regulates Sec8–PSD-95 complex formation.\",\n      \"method\": \"Co-immunoprecipitation from brain tissue, peptide competition assay, immunoblotting of subcellular fractions, deletion/mutation analysis of the C-terminal TTV motif\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus competition assay, single lab, two orthogonal approaches\",\n      \"pmids\": [\"12675619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In Drosophila, Sec8 is required in vivo for regulation of synaptic microtubule density (approximately doubled in sec8 null mutants) and influences synaptic growth and glutamate receptor trafficking at the neuromuscular junction; no requirement for basal neurotransmission was detected.\",\n      \"method\": \"Forward genetic screen, generation of sec8 null mutants, immunocytochemistry with anti-Sec8 antibodies, synaptic electrophysiology, immunoblotting for maternal contribution\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null mutant with multiple phenotypic readouts (morphology, electrophysiology), single study\",\n      \"pmids\": [\"16351720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sec8 (EXOC4) colocalizes, co-immunoprecipitates, and co-fractionates with the myelin protein OSP/Claudin11 and with the scaffolding protein CASK in oligodendrocytes. Sec8 overexpression promotes oligodendrocyte morphological differentiation and myelin-like membrane formation in vitro, whereas siRNA-mediated Sec8 knockdown inhibits this process, placing Sec8 as a central regulator of vesicle recruitment to sites of myelin membrane growth.\",\n      \"method\": \"Co-immunoprecipitation, co-fractionation, immunofluorescence colocalization, Sec8 overexpression and siRNA knockdown with morphological/differentiation readouts, anti-Sec8 antibody perturbation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional gain/loss-of-function, single lab\",\n      \"pmids\": [\"16478790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Schwann cells, Sec8 (EXOC4) interacts with Dlg1 (Discs large 1); this interaction promotes membrane addition during myelination. In the Mtmr2-null model of myelin outfoldings, the Dlg1–Sec8 interaction contributes to excess membrane formation, while Dlg1–Mtmr2 interaction negatively regulates membrane formation.\",\n      \"method\": \"Co-immunoprecipitation in Schwann cells, Mtmr2-null mouse model, Schwann cell/DRG coculture with Mtmr2 rescue, immunofluorescence localization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic model with functional rescue, single lab\",\n      \"pmids\": [\"19587293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Insulin stimulates phosphorylation of Sec8 (EXOC4) at Ser-32 in 3T3-L1 adipocytes via a PI3K-dependent pathway (likely Akt); however, overexpression of non-phosphorylatable S32A or phosphomimetic S32E Sec8 mutants had no detectable effect on insulin-stimulated GLUT4 or transferrin receptor trafficking to the plasma membrane.\",\n      \"method\": \"Phosphoproteomics (mass spectrometry), pharmacological inhibition (wortmannin), overexpression of phosphorylation-site mutants (S32A, S32E), surface GLUT4/TfR assay\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in-cell phosphorylation identified by MS plus mutagenesis, but functional effect on GLUT4 was explicitly negative; negative result recorded accordingly\",\n      \"pmids\": [\"19006485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Schizosaccharomyces pombe, Sec8p is required for mating-specific cell adhesion, and both Sec8p and Exo70p are required for proper spore cell wall development, demonstrating distinct roles for different exocyst subunits in sexual development.\",\n      \"method\": \"sec8-1 temperature-sensitive mutant and exo70Δ null analysis, immunofluorescence (Meu14p localization), genetic epistasis/complementation\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetics with specific phenotypic readouts, single lab fission yeast study\",\n      \"pmids\": [\"20180855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sec8 (EXOC4) knockdown in oral squamous cell carcinoma cells reduces cellular invasion and secretion of matrix metalloproteinases MMP-2 and MMP-9 (by gelatin zymography), consistent with a role for Sec8 in tethering MMP-containing secretory vesicles to the plasma membrane.\",\n      \"method\": \"siRNA knockdown, invasion assay, gelatin zymography for MMP secretion, proliferation assay\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single siRNA knockdown approach with phenotypic readouts but no direct pathway dissection\",\n      \"pmids\": [\"23207790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sec8 (EXOC4) knockdown promotes G1/S cell cycle arrest by increasing p21(Cip1) expression via stabilization of FOXO transcription factors; Sec8 normally promotes FOXO ubiquitin-proteasome degradation through regulation of Mdm2 (but not Skp2), and its loss also reduces retinoblastoma protein phosphorylation.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (flow cytometry), immunoblotting for p21/FOXO/Mdm2/Skp2/pRb, proteasome inhibitor experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown plus western blotting, no direct biochemical reconstitution\",\n      \"pmids\": [\"24299491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sec8 (EXOC4) binds JIP4 (JNK-interacting protein 4); Sec8 knockdown enhances JIP4 binding to MKK4, resulting in decreased phosphorylation of MKK4, JNK, and p38 MAPK, thereby suppressing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phosphorylation assays (western blot for pMKK4, pJNK, pp38), apoptosis assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP plus knockdown, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"25244576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec8 (EXOC4) knockdown suppresses cell migration by reducing phosphorylation of cytokeratin8 at Ser73; this is mediated through activation of ERK and p38 MAPK signaling pathways via downregulation of PAK (p21-activated kinase) activity, itself regulated by Pirh2 and Siah1 E3 ligases.\",\n      \"method\": \"siRNA knockdown, migration assay, phospho-specific immunoblotting for CK8-pSer73 and MAPK pathway components, rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with western blot readouts, indirect pathway placement\",\n      \"pmids\": [\"25725287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sec8 (EXOC4) knockdown decreases Smad3 and Smad4 expression at the basal transcriptional level (dependent on CBP/CREB-binding protein), thereby reducing N-cadherin expression and modulating TGF-β-induced epithelial-mesenchymal transition and cell migration/adhesion.\",\n      \"method\": \"siRNA knockdown of Sec8 and CBP, RT-PCR and immunoblotting for N-cadherin, Smad3, Smad4, CBP; cell migration and adhesion assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown plus western blot, no direct biochemical interaction demonstrated\",\n      \"pmids\": [\"27769780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREG1 directly interacts with Sec8 (EXOC4) of the exocyst complex; this interaction is required for cardiomyocyte differentiation and cell cohesion. CREG1, Sec8, and N-cadherin colocalize at intercalated discs in vivo and at cell-cell junctions in cultured cardiomyocytes. CREG1 knockout disrupts the Sec8–N-cadherin interaction and induces their degradation, while CREG1 overexpression enhances adherens and gap junction assembly.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of CREG1, rescue of CREG1 KO ES cells, immunofluorescence colocalization, gain/loss-of-function differentiation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis-based rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27334848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRK2 interacts with Sec8 (EXOC4); LRRK2 kinase activity and presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits, and overexpression of Sec8 significantly rescues the pathological effects of the LRRK2 G2019S Parkinson's disease mutation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of Sec8 in LRRK2 G2019S cells, exocyst subunit co-assembly assays, rescue phenotype analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP plus overexpression rescue, no in vitro reconstitution\",\n      \"pmids\": [\"33498474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EXOC4 (Sec8) promotes diffuse-type gastric cancer cell migration/invasion and tumor metastasis by stimulating secretion of integrin α5/β1 and EGF, enhancing integrin/EGFR–FAK interaction, and increasing phosphorylation of FAK at Y397; the FAK inhibitor VS-4718 reverses EXOC4-driven metastasis.\",\n      \"method\": \"LC-MS/MS proteomics identification, siRNA knockdown and overexpression, migration/invasion assays, phospho-FAK immunoblotting, co-immunoprecipitation (FAK–integrin/EGFR), xenograft and patient-derived xenograft models, pharmacological FAK inhibition\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, phosphoblotting, in vivo PDX, pharmacological rescue), single lab\",\n      \"pmids\": [\"35471457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure (2.5 Å) of the C-terminal half of Sec8 (EXOC4) containing the ITTV PDZ-binding motif reveals an unusually long C-terminal helix with a 14-residue 'spacer' bridging the ITTV motif to the compact Sec8 core. Sec8 preferentially binds PDZ2 over PDZ1 and PDZ3 of SAP102; deletion of the spacer completely abolishes binding to SAP102.\",\n      \"method\": \"X-ray crystallography (2.5 Å resolution), in vitro binding assays, deletion mutagenesis of the spacer region, computational modeling\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis and binding assays, single lab but orthogonal methods\",\n      \"pmids\": [\"37849738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EXOC4 (Sec8) stabilizes STING1 by suppressing K27-linked ubiquitination at STING1 residues K338, K347, and K370 catalyzed by the E3 ligase FBXL19, thereby preventing SQSTM1-mediated autophagic degradation of STING1 and promoting type I interferon signaling in response to DNA viruses. Conditional Exoc4/Sec8 knockout mice show increased susceptibility to HSV-1 infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping/mutagenesis, EXOC4 knockdown/overexpression, IFN reporter assays, antiviral replication assays, conditional knockout mouse model, microscale thermophoresis (MST) for binding\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, mutagenesis, MST, KO mouse), single lab\",\n      \"pmids\": [\"40413753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sec8 (EXOC4) stabilizes RIG-I by competing with the E3 ligase STUB1 for binding to RIG-I's CARD domain, thereby inhibiting STUB1-mediated K48-linked ubiquitination of RIG-I at Lys190 and its proteasomal degradation. Additionally, Sec8 reduces STUB1 mRNA by suppressing p53 expression. Sec8-deficient mice show increased susceptibility to RNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation (Sec8–RIG-I, STUB1–RIG-I), ubiquitination assays with site-specific mutants (RIG-I K190), Sec8 KO mice, in vivo and in vitro antiviral assays, p53/STUB1 expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ubiquitination site mutagenesis, in vivo KO mouse, single lab multiple methods\",\n      \"pmids\": [\"41580425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"p300-mediated acetylation of EXOC4 at lysine 433 induces its nuclear translocation. In the nucleus, EXOC4 facilitates the interaction between PRMT5 and KU70, enabling PRMT5-catalyzed methylation of KU70 at arginine 318, which increases KU complex DNA-binding affinity and accelerates double-strand break repair by non-homologous end joining (NHEJ), thereby promoting chemoradiotherapy resistance in gastric cancer.\",\n      \"method\": \"Site-directed mutagenesis (K433), nuclear fractionation, co-immunoprecipitation (EXOC4–PRMT5–KU70), PRMT5 methylation assay, DNA-binding affinity assay, inhibitory peptide targeting K433, preclinical xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus co-IP plus in vivo preclinical models, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"41826730\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOC4/Sec8 is a core subunit of the evolutionarily conserved ~1–2 MDa exocyst complex that tethers secretory vesicles to specific plasma membrane docking sites; beyond this canonical vesicle-tethering role (supported by yeast biochemistry and structural studies), EXOC4 regulates synaptic microtubule density and myelination, binds synaptic scaffold proteins PSD-95 and SAP102 via its C-terminal ITTV/TTV PDZ-binding motif (structurally characterized at 2.5 Å), controls cell cycle progression and migration through FOXO/p21 and MAPK pathways, promotes antiviral innate immunity by stabilizing both STING1 (against DNA viruses, via suppression of FBXL19-mediated K27-ubiquitination) and RIG-I (against RNA viruses, via competition with STUB1-mediated K48-ubiquitination), and—in a non-canonical nuclear role—undergoes p300-acetylation at K433 to translocate to the nucleus where it facilitates PRMT5-mediated KU70 methylation and NHEJ-dependent DNA repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOC4/Sec8 is a core subunit of the conserved ~1\\u20132 MDa exocyst complex that tethers secretory vesicles to plasma membrane docking sites and acts downstream of the Rab GTPase Sec4 to direct vesicle fusion [#0, #1]. This tethering function underlies essential physiological roles, including paraxial mesoderm formation during mouse gastrulation [#2] and, in fungal systems, mating-specific cell adhesion and spore cell wall development [#8]. In neural tissue, Sec8 regulates synaptic microtubule density, synaptic growth, and glutamate receptor trafficking [#4], and engages synaptic scaffold proteins of the PSD-95/SAP102 (MAGUK) family through a C-terminal TTV/ITTV PDZ-binding motif; structural analysis shows that an unusually long C-terminal helix with a 14-residue spacer bridges the ITTV motif to the Sec8 core and confers preferential binding to the PDZ2 domain of SAP102 [#3, #17]. Through interactions with scaffolds such as CASK and Dlg1, Sec8 directs vesicle recruitment to sites of myelin membrane growth in oligodendrocytes and Schwann cells [#5, #6], and its binding to CREG1 stabilizes a Sec8\\u2013N-cadherin axis required for cardiomyocyte differentiation and cell-cell junction assembly [#14]. EXOC4 also promotes tumor cell migration and invasion by enhancing secretion of integrin \\u03b15\\u03b21 and EGF and driving integrin/EGFR\\u2013FAK signaling [#16]. Beyond vesicle tethering, EXOC4 stabilizes antiviral sensors: it suppresses FBXL19-mediated K27-linked ubiquitination of STING1 to block its autophagic degradation and sustain type I interferon responses to DNA viruses [#18], and competes with STUB1 for the RIG-I CARD domain to inhibit K48-linked ubiquitination and degradation of RIG-I against RNA viruses [#19]. In a non-canonical nuclear role, p300-mediated acetylation of EXOC4 at K433 drives nuclear translocation, where EXOC4 bridges PRMT5 and KU70 to enable arginine methylation of KU70 and enhance NHEJ-dependent double-strand break repair [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that Sec8 is not a free protein but part of a discrete particle acting downstream of a Rab GTPase, framing it as an effector that targets vesicle fusion to the plasma membrane.\",\n      \"evidence\": \"Subcellular fractionation, sucrose gradient sedimentation, gel filtration and cross-linking with Sec4 co-fractionation in yeast\",\n      \"pmids\": [\"1512289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve full subunit composition\", \"Mechanism of Sec4-dependent activation not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined Sec8 as a stable subunit of a multisubunit ~1\\u20132 MDa complex (the exocyst) localized to sites of active exocytosis, establishing the molecular machine in which EXOC4 operates.\",\n      \"evidence\": \"His-tag affinity chromatography, co-IP of tagged Sec8, gel filtration, sedimentation, and immunofluorescence in S. cerevisiae\",\n      \"pmids\": [\"7615633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry and architecture not resolved\", \"No structural model of intact complex\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated an essential in vivo developmental requirement for Sec8, moving it beyond a yeast housekeeping factor to a metazoan morphogenetic regulator.\",\n      \"evidence\": \"Gene-trap loss-of-function in mouse embryos with gastrulation phenotype analysis\",\n      \"pmids\": [\"9441674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific secretory cargo driving the phenotype unknown\", \"Did not separate exocyst-dependent from independent roles\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the C-terminal TTV motif as a PDZ-binding module linking Sec8 to the postsynaptic scaffold PSD-95, providing a mechanism for targeting the exocyst to synaptic sites.\",\n      \"evidence\": \"Brain co-IP, peptide competition, and C-terminal motif deletion/mutation\",\n      \"pmids\": [\"12675619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of synaptic targeting not tested in vivo\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed Sec8 controls synaptic microtubule density and receptor trafficking, distinguishing a structural/cargo-targeting role from basal neurotransmission.\",\n      \"evidence\": \"Drosophila sec8 null mutants with immunocytochemistry, electrophysiology, and morphological readouts\",\n      \"pmids\": [\"16351720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between exocyst and microtubule regulation unresolved\", \"Mammalian conservation not shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed Sec8 as a regulator of vesicle recruitment to growing myelin membrane via interactions with CASK and OSP/Claudin11.\",\n      \"evidence\": \"Co-IP, co-fractionation, colocalization, and gain/loss-of-function in oligodendrocytes\",\n      \"pmids\": [\"16478790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Claudin11 interaction not dissected\", \"In vivo myelination requirement not tested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the myelination role to Schwann cells through a Dlg1\\u2013Sec8 axis that drives membrane addition, linked to a disease model of myelin outfoldings.\",\n      \"evidence\": \"Co-IP in Schwann cells plus Mtmr2-null mouse model with coculture rescue\",\n      \"pmids\": [\"19587293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of Sec8 to membrane excess not isolated\", \"Direct binding interface undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Tested whether insulin/PI3K signaling regulates Sec8 to control GLUT4 trafficking; identified a phosphosite but found no functional effect, constraining models of insulin-regulated exocytosis.\",\n      \"evidence\": \"Phosphoproteomics, wortmannin inhibition, and S32A/S32E mutant overexpression in adipocytes\",\n      \"pmids\": [\"19006485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of Ser32 phosphorylation unknown (negative result)\", \"Other regulatory sites not examined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed subunit-specific exocyst functions in fungal sexual development, indicating EXOC4 contributes non-redundant roles distinct from other subunits.\",\n      \"evidence\": \"sec8-1 ts and exo70\\u0394 mutants with localization and genetic epistasis in S. pombe\",\n      \"pmids\": [\"20180855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of subunit specialization unknown\", \"Relevance to metazoan EXOC4 unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a direct CREG1\\u2013Sec8 interaction stabilizing a Sec8\\u2013N-cadherin complex required for cardiomyocyte differentiation and junction assembly.\",\n      \"evidence\": \"Reciprocal co-IP, CREG1 mutagenesis/rescue in ES cells, colocalization, and differentiation assays\",\n      \"pmids\": [\"27334848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether N-cadherin is an exocyst cargo or stable partner unresolved\", \"Mechanism of CREG1-dependent stabilization undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a pro-metastatic secretory program in which EXOC4 drives integrin/EGF secretion and FAK activation, with pharmacological FAK inhibition reversing the phenotype.\",\n      \"evidence\": \"LC-MS/MS, knockdown/overexpression, phospho-FAK blotting, co-IP, PDX models, and FAK inhibitor rescue in gastric cancer\",\n      \"pmids\": [\"35471457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effect is purely exocyst tethering vs additional signaling unclear\", \"Direct EXOC4 cargo selectivity not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided structural mechanism for Sec8\\u2013MAGUK targeting, showing a long C-terminal helix and spacer required for selective binding to SAP102 PDZ2.\",\n      \"evidence\": \"2.5 \\u00c5 crystal structure, in vitro binding, and spacer deletion mutagenesis\",\n      \"pmids\": [\"37849738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of PDZ2 selectivity in neurons not tested\", \"Structure limited to C-terminal half\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-canonical innate-immune function: EXOC4 stabilizes STING1 against FBXL19-mediated K27 ubiquitination and autophagic degradation to sustain anti-DNA-virus interferon responses.\",\n      \"evidence\": \"Co-IP, ubiquitination site mapping, MST binding, IFN/antiviral assays, and conditional KO mice challenged with HSV-1\",\n      \"pmids\": [\"40413753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization requires intact exocyst unknown\", \"Mechanism of competition with FBXL19 not structurally defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended antiviral function to RNA virus sensing by showing EXOC4 protects RIG-I from STUB1-mediated K48 ubiquitination and degradation, partly via p53/STUB1 suppression.\",\n      \"evidence\": \"Reciprocal co-IP, RIG-I K190 ubiquitination mutants, p53/STUB1 analysis, and KO mice in antiviral assays\",\n      \"pmids\": [\"41580425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition interface with STUB1 not structurally resolved\", \"Link between exocyst tethering role and immune stabilization unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a nuclear, repair-promoting role for EXOC4 in which K433 acetylation drives translocation and EXOC4 bridges PRMT5\\u2013KU70 to enhance NHEJ and therapy resistance.\",\n      \"evidence\": \"K433 mutagenesis, nuclear fractionation, co-IP, PRMT5 methylation and DNA-binding assays, inhibitory peptide, and xenografts\",\n      \"pmids\": [\"41826730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a cytoplasmic exocyst subunit acquires DNA-repair scaffolding function unexplained\", \"Generality beyond gastric cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EXOC4 partitions between its canonical exocyst tethering role and its emerging non-canonical functions in innate immunity and nuclear DNA repair, and what determines this functional switching, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking exocyst, immune, and nuclear roles\", \"Regulatory switch (acetylation, complex assembly) controlling localization undefined\", \"Human structural model of intact exocyst absent from this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 14, 17, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"PSD-95\", \"SAP102\", \"CASK\", \"DLG1\", \"CREG1\", \"STING1\", \"RIG-I\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}