{"gene":"EXOC5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1997,"finding":"Human Sec10p (hSec10p) was identified as a 77-kDa protein component of the mammalian exocyst complex, with broad tissue distribution. Co-transfection of hSec10p and mammalian Sec8p in COS cells demonstrated identical subcellular distribution including peripheral cytoplasmic localization, establishing hSec10p as a mammalian exocyst subunit involved in post-Golgi traffic.","method":"Cloning, Northern/Western blot, immunofluorescence co-localization in co-transfected COS cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and expression data from single lab, co-transfection but no co-IP or reconstitution reported in abstract","pmids":["9119050"],"is_preprint":false},{"year":1998,"finding":"Yeast Sec10p has two functional domains: the N-terminal two-thirds directly interacts with exocyst component Sec15p, and overexpression of this domain displaces full-length Sec10 from the exocyst complex, causing a block in exocytosis and accumulation of secretory vesicles. The C-terminal domain does not interact with other exocyst members and does not cause a secretory defect, but instead is required for morphogenesis (cell elongation), suggesting Sec10p has bifunctional roles in exocytosis and morphogenesis.","method":"Dominant-negative mutagenesis, biochemical fractionation, phenotypic analysis in S. cerevisiae","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple domain mutants with distinct phenotypes, biochemical displacement of complex, replicated genetic approach in yeast ortholog","pmids":["9658167"],"is_preprint":false},{"year":2002,"finding":"Drosophila Sec10 (dSec10) is essential for endocrine (steroid hormone) secretion in the ring gland. Tissue-specific RNAi knockdown showed no essential requirement in nervous system, musculature, gut, or epidermis, and no defects in neuromuscular synapse morphogenesis or neurotransmission. Developmental arrest from dSec10 RNAi was partially rescued by feeding ecdysone, demonstrating a specific role in steroid hormone secretion rather than general exocytosis.","method":"Transgenic RNAi knockdown, tissue-specific rescue with ecdysone feeding, neuromuscular synapse morphology and physiology assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment, multiple tissue-specific knockdowns with orthogonal assays, pharmacological rescue","pmids":["12453153"],"is_preprint":false},{"year":2009,"finding":"Exocyst protein Sec10 regulates primary ciliogenesis in MDCK renal epithelial cells. shRNA knockdown of Sec10 results in primary cilia containing only basal bodies (no axoneme extension), while Sec10 overexpression increases ciliogenesis. Sec10 knockdown also prevents normal cyst morphogenesis in collagen matrix. Par3 co-localizes with and co-immunoprecipitates with the exocyst, consistent with a role in targeting vesicles for ciliogenesis. Rescue with shRNA-resistant human Sec10 confirmed specificity.","method":"shRNA knockdown, stable overexpression, immunofluorescence, scanning and transmission electron microscopy, co-immunoprecipitation, collagen matrix cystogenesis assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, IF, co-IP), genetic rescue, both loss- and gain-of-function in single study","pmids":["19297529"],"is_preprint":false},{"year":2011,"finding":"Sec10 biochemically interacts with ciliary proteins polycystin-2 (PKD2), IFT88, and IFT20 by co-immunoprecipitation, and co-localizes with polycystin-2 at the primary cilium. Sec10 knockdown in MDCK cells causes loss of flow-generated calcium increases, hyperproliferation, and abnormal MAPK activation. In zebrafish, sec10 morpholino knockdown phenocopies pkd2 knockdown (curly tail, left-right patterning defects, glomerular expansion), and sec10/pkd2 double knockdown shows synergistic genetic interaction, supporting a model where the exocyst is required for ciliary localization of polycystin-2.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, zebrafish morpholino knockdown, genetic epistasis (synergistic interaction), calcium imaging, MAPK activity assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction, genetic epistasis in vivo, multiple orthogonal phenotypic readouts across two model systems","pmids":["21490950"],"is_preprint":false},{"year":2012,"finding":"Sec10 biochemically interacts with the translocon subunit Sec61β (by GST pulldown), and is preferentially recruited to ER membranes during basolateral (not apical) protein synthesis. In cell-free translation/translocation assays, exocyst depletion enhanced recruitment to ER membranes during basolateral G protein of VSV translation compared to apical hemagglutinin translation. Sec10 overexpression increases Sec61β phosphorylation, suggesting a regulatory role in basolateral protein translocation at the rough ER.","method":"GST pulldown, cell-free translation/translocation assay, 32P-orthophosphate labeling and immunoprecipitation","journal":"Nephron. Experimental nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro assay and pulldown but single lab, limited mechanistic follow-up reported in abstract","pmids":["23037926"],"is_preprint":false},{"year":2014,"finding":"Sec10 (exocyst) biochemically interacts with the epidermal growth factor receptor (EGFR) by co-immunoprecipitation. Sec10-overexpressing cells show greater phospho-ERK levels in response to EGF, increased EGFR endocytosis, and are protected from cell injury. Gefitinib (EGFR inhibitor) and Dynasore (dynamin inhibitor) both reduce EGFR endocytosis; inhibition of MAPK reduces EGFR endocytosis, suggesting a feedback loop. Gefitinib reverses the protective effect of Sec10 overexpression, causally linking the Sec10-EGFR-endocytosis-MAPK axis to cellular protection.","method":"Co-immunoprecipitation, pharmacological inhibition (gefitinib, U0126, Dynasore), EGFR endocytosis assay, cell injury assay, zebrafish morpholino knockdown","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with pharmacological rescue and in vivo zebrafish validation, single lab but multiple orthogonal approaches","pmids":["25298525"],"is_preprint":false},{"year":2014,"finding":"In C. elegans intestine, SEC-10 (exocyst subunit) is required for formation of endosomal tubular networks needed for basolateral recycling of clathrin-independent endocytic (CIE) cargoes (hTAC, GLUT1, DAF-4). Depletion of SEC-10 or other exocyst subunits converts tubular endosomes to ring-like structures. Epistasis analysis placed SEC-10 at an intermediate step between early endosomes and recycling endosomes. SEC-10 coordinates with RAB-10 and microtubules to maintain the endosomal tubular network.","method":"RNAi depletion, live-cell imaging of endosomal structures, genetic epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis placing SEC-10 in pathway, multiple exocyst subunit depletions, multiple cargo types, C. elegans ortholog","pmids":["25301900"],"is_preprint":false},{"year":2015,"finding":"Sec10 is required for urothelial barrier integrity during development. Conditional knockout of Sec10 in ureteric bud-derived cells (Ksp1.3-Cre) caused decreased uroplakin-3 at the luminal apical surface (by E16.5) and complete absence by E17.5, followed by urothelial degeneration and ureteropelvic junction obstruction. This demonstrates that Sec10-mediated exocytosis is required for apical delivery of uroplakin proteins to establish the urothelial barrier.","method":"Conditional knockout mouse (Cre-lox), immunofluorescence for uroplakin-3 localization, histology","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — first conditional Sec10 KO with mechanistic endpoint (uroplakin trafficking defect) and temporal characterization","pmids":["26046524"],"is_preprint":false},{"year":2015,"finding":"Sec10 and Cdc42 act in the same genetic pathway during retinal development in zebrafish. Sec10 morpholino knockdown causes loss of outer nuclear layer and irregular RPE, with an intracellular melanosome transport defect (retrograde). Sub-optimal co-injection of sec10 and cdc42 morpholinos produced synergistic phenotypes, establishing genetic interaction. Sec10 is required for outer segment development of photoreceptors, likely by trafficking proteins necessary for ciliogenesis.","method":"Morpholino knockdown, synergistic genetic interaction analysis, melanosome transport assay, histology, transmission electron microscopy","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by synergy test, multiple readouts, single lab","pmids":["26024121"],"is_preprint":false},{"year":2015,"finding":"Sec10 knockdown in MDCK cells causes increased basal apoptotic cell extrusion, increased sensitivity to apoptotic triggers, and altered mitotic spindle angles (planar cell polarity defect) during 3D cystogenesis in collagen, without disrupting apico-basal polarity. These phenotypes were rescued by shRNA-resistant human Sec10. Kidney-specific Sec10 KO mice also showed defects in primary cilia assembly and abnormal epithelial cell extrusion in renal tubules.","method":"shRNA knockdown, genetic rescue, 3D collagen culture cystogenesis, apoptosis assay, mitotic spindle angle measurement, conditional KO mouse histology","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue confirms specificity, multiple in vitro and in vivo readouts, single lab","pmids":["26040895"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of near-full-length zebrafish Sec10 was solved at 2.73 Å resolution. The structure consists of tandem antiparallel helix bundles forming a straight rod, consistent with helical core regions of other exocyst subunits, providing the first atomic-level structural details of Sec10.","method":"X-ray crystallography","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.73 Å, near-full-length protein, direct structural determination","pmids":["28098232"],"is_preprint":false},{"year":2018,"finding":"In the moss Physcomitrella patens, For1F encodes a fusion protein of Sec10 (exocyst subunit) and formin (actin nucleation factor). Reduction of For1F or actin filaments inhibits exocytosis. For1F dynamically associates with Sec6 (another exocyst subunit) in an actin-dependent manner. Complementation experiments showed either half alone can rescue loss of For1F, indicating the fusion is not essential but actin filaments are required for exocyst-mediated exocytosis.","method":"Genetic complementation, live-cell imaging of protein dynamics, actin disruption, exocytosis assay in Physcomitrella patens","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation and dynamic imaging, but non-mammalian/plant ortholog system; actin-regulation of exocyst is mechanistically informative for Sec10 function","pmids":["29374070"],"is_preprint":false},{"year":2018,"finding":"Conditional deletion of Exoc5 (EXOC5) in cochlear hair cells (Gfi1Cre) or otic epithelium (rAAV-iCre) results in apoptosis of hair cells with stereociliary bundle disorganization and apoptotic degeneration of spiral ganglion neurons, demonstrating that Exoc5 is required for survival and maintenance of cochlear hair cells and spiral ganglion neurons.","method":"Conditional knockout mice (two independent Cre lines), in utero rAAV delivery, auditory function testing, histology, immunofluorescence","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent KO models converge on same cell survival phenotype, single lab","pmids":["29327200"],"is_preprint":false},{"year":2018,"finding":"Sec10 overexpression in MDCK cells inhibits wound healing and ruffle formation, while Sec10 knockdown accelerates both. Sec10-overexpressing cells have higher amounts of diacylglycerol kinase (DGK) gamma at the leading edge, and a DGK inhibitor reverses the inhibition of wound healing and ruffle formation in Sec10-overexpressing cells. This establishes a Sec10-DGKγ regulatory axis in cell migration.","method":"Scratch wound assay, immunofluorescence of DGK gamma localization, pharmacological DGK inhibition, shRNA knockdown and stable overexpression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue links DGKγ to Sec10-mediated migration effect, but single lab and single paper","pmids":["29326040"],"is_preprint":false},{"year":2021,"finding":"Conditional loss of Exoc5 in retinal pigment epithelium (RPE) of mice causes progressive retinal thinning, abnormal RPE pigmentation, reduced RPE65 levels, reduced c-wave amplitude (dysfunctional RPE), and loss of visual pigments. Exoc5-/- zebrafish show smaller eyes with decreased RPE melanocytes and shorter photoreceptor outer segments with loss of rod and cone opsins, indicating exocyst-mediated trafficking in RPE is required for RPE structure and photoreceptor maintenance.","method":"RPE-specific conditional knockout mouse, zebrafish exoc5 mutant, electroretinography (c-wave), histology, immunofluorescence","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent animal models converge on RPE trafficking phenotype, single lab","pmids":["34064901"],"is_preprint":false},{"year":2024,"finding":"Oocyte-specific deletion of Exoc5 (Zp3-Exoc5-cKO) causes female infertility. The first follicular wave proceeds to the antral stage but produces developmentally incompetent oocytes (failed IVF). Subsequent adult follicular waves do not progress beyond the secondary follicle stage and undergo apoptosis, demonstrating that EXOC5 is required for folliculogenesis and oocyte developmental competence.","method":"Oocyte-specific conditional knockout mouse (Zp3-Cre), IVF, histology, follicle staging","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific phenotypic readouts, single lab","pmids":["39037927"],"is_preprint":false},{"year":2025,"finding":"Sec10 negatively regulates antiviral JAK-STAT signaling by interacting with E3 ubiquitin ligase STUB1, promoting STUB1-STAT1 interaction, and accelerating STUB1-mediated proteasomal degradation of STAT1 via K6-linked polyubiquitination at Lys240 and Lys652. Myeloid-specific deletion of Sec10 in mice enhances IFN-I response to viral infection and improves survival.","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, proteasome inhibitor treatment, myeloid-specific conditional KO mice, viral infection survival assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific ubiquitination sites identified by mutagenesis, co-IP of complex, in vivo KO confirmation, multiple orthogonal methods","pmids":["40920886"],"is_preprint":false},{"year":2025,"finding":"Sec10 negatively regulates antiviral innate immunity by suppressing RIG-I transcription through inactivation of the NRF2-ATF4 axis. ATF4 binds the RIG-I promoter to promote transcription; NRF2 upregulates ATF4; Sec10 triggers inactivation of NRF2-ATF4 during RNA viral infection, thereby restraining RIG-I expression and IFN-I response. Sec10 deficiency enhances innate immunity and reduces viral load in mice.","method":"Transcriptional reporter assays, promoter binding analysis, siRNA knockdown, in vivo Sec10-deficient mice, viral load measurement","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis established, in vivo validation, single lab","pmids":["41079927"],"is_preprint":false},{"year":2026,"finding":"EXOC5 facilitates autophagic degradation of STING1 via K63-linked polyubiquitination at Lys224 and Lys338 by E3 ligase TRIM56, which acts as a recognition signal for cargo receptor SQSTM1/p62, thereby attenuating cGAS-STING1-mediated antiviral IFN-I signaling and promoting DNA virus replication. Myeloid-specific Exoc5 deletion in mice improves survival and reduces viral load.","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, autophagy flux assay (bafilomycin A1), siRNA knockdown, myeloid-specific KO mice, viral infection model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific ubiquitination sites by mutagenesis, co-IP of EXOC5-TRIM56-STING1-SQSTM1 complex, autophagic mechanism confirmed, in vivo KO validation","pmids":["41968661"],"is_preprint":false},{"year":2026,"finding":"Myeloid-specific Exoc5 deficiency in macrophages reduces exosome release, leading to intracellular accumulation of formin1. This enhances macrophage migration in an actin- and formin1-dependent manner (reversed by actin disruptor and formin1 inhibitor but not Rac1 inhibitor). Enhanced macrophage migration into the kidney causes inflammation and hypertension.","method":"Myeloid-specific conditional KO mice (LysM-Cre), exosome quantification, pharmacological inhibition (actin disruptor, formin1 inhibitor, Rac1 inhibitor), macrophage migration assay, adoptive transfer experiment","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of pathway, in vivo transfer experiment, single lab","pmids":["41604889"],"is_preprint":false},{"year":2026,"finding":"SEC10 suppresses JAK1 transcription in a KLF15-dependent manner during BoHV-1 infection. SEC10 downregulates the transcription factor KLF15, which normally promotes JAK1 transcription, thereby establishing a SEC10-KLF15-JAK1 regulatory axis that dampens JAK-STAT-mediated antiviral IFN-I immunity and promotes BoHV-1 replication.","method":"siRNA knockdown, transcriptional reporter assays, co-immunoprecipitation, promoter analysis, viral replication assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway mechanistically defined by multiple reporters and knockdown, single lab","pmids":["41903488"],"is_preprint":false},{"year":2026,"finding":"Exoc5 deficiency in kidney proximal tubule cells increases YAP expression and YAP target genes (CTGF, CYR61), and exacerbates TGF-β-induced epithelial-to-mesenchymal transition and fibrosis following ureteral obstruction. In HK-2 cells, siRNA knockdown of EXOC5 increased both YAP and Pax2 expression, linking Exoc5 to regulation of YAP signaling and tubular cell differentiation.","method":"Proximal tubule-specific conditional KO mouse (PEPCK-Cre), unilateral ureteral obstruction model, siRNA knockdown in HK-2 cells, Western blot for YAP/CTGF/CYR61/Pax2","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and in vitro siRNA converge on same pathway, single lab","pmids":["41781492"],"is_preprint":false}],"current_model":"EXOC5/Sec10 is a central structural subunit of the heterooctameric exocyst complex that functions as a bifunctional scaffold: its N-terminal domain directly binds Sec15p to maintain exocyst integrity and drive polarized secretory vesicle docking at the plasma membrane, while its C-terminal helical rod domain (visualized by crystal structure) is required for morphogenesis; in mammalian and model organism systems, Sec10 regulates primary ciliogenesis (by mediating ciliary delivery of polycystin-2, IFT88, and IFT20), basolateral protein translocation at the rough ER (via interaction with Sec61β), EGFR endocytosis-dependent MAPK signaling, epithelial barrier maintenance (apical uroplakin delivery), cell migration (through DGKγ and formin1), and innate immune suppression (by promoting STUB1-mediated K6-ubiquitination and proteasomal degradation of STAT1, and TRIM56-mediated K63-ubiquitination and autophagic degradation of STING1)."},"narrative":{"mechanistic_narrative":"EXOC5/Sec10 is a structural subunit of the heterooctameric exocyst complex that drives polarized exocytosis by tethering post-Golgi secretory vesicles for docking at the plasma membrane [PMID:9119050, PMID:9658167]. It is a bifunctional scaffold: its N-terminal two-thirds directly binds the exocyst subunit Sec15p to maintain complex integrity and support exocytosis, while its C-terminal helical-rod domain — visualized as tandem antiparallel helix bundles by crystallography — is separately required for morphogenesis [PMID:9658167, PMID:28098232]. Through this exocyst-tethering activity EXOC5 governs primary ciliogenesis in renal epithelia, mediating ciliary delivery of polycystin-2 (PKD2), IFT88, and IFT20, with loss of EXOC5 abolishing axoneme extension, flow-induced calcium signaling, and normal cyst morphogenesis [PMID:19297529, PMID:21490950]. EXOC5-dependent trafficking is required for apical and basolateral cargo delivery across epithelia, including uroplakin-3 deposition for urothelial barrier formation and CIE-cargo recycling through endosomal tubular networks coordinated with RAB-10 [PMID:25301900, PMID:26046524]. EXOC5 supports cell survival and tissue maintenance in cochlear hair cells and spiral ganglion neurons, retinal pigment epithelium and photoreceptors, and developing oocytes, and modulates cell migration through DGKγ and formin1 [PMID:29327200, PMID:34064901, PMID:39037927, PMID:29326040]. Beyond secretion, EXOC5 is a negative regulator of antiviral type-I interferon signaling: it promotes STUB1-mediated K6-linked polyubiquitination and proteasomal degradation of STAT1, TRIM56-mediated K63-linked polyubiquitination and SQSTM1/p62-dependent autophagic degradation of STING1, and transcriptional suppression of RIG-I and JAK1 [PMID:40920886, PMID:41968661, PMID:41079927, PMID:41903488]. In the kidney, EXOC5 also restrains YAP signaling and TGF-β-driven epithelial-to-mesenchymal transition and fibrosis [PMID:41781492].","teleology":[{"year":1997,"claim":"Established that a mammalian Sec10 ortholog exists as a bona fide exocyst subunit, extending yeast secretory machinery to human post-Golgi traffic.","evidence":"Cloning of human Sec10p with Northern/Western analysis and co-localization with Sec8p in co-transfected COS cells","pmids":["9119050"],"confidence":"Medium","gaps":["Co-localization only, no co-IP or reconstitution of the mammalian complex","Cargo and functional role not defined"]},{"year":1998,"claim":"Defined Sec10 as a bifunctional protein with separable domains, answering how one subunit can serve both exocytosis and morphogenesis.","evidence":"Domain-mapping dominant-negative mutants, biochemical fractionation, and phenotypic analysis in S. cerevisiae showing N-terminal Sec15p binding and C-terminal morphogenesis role","pmids":["9658167"],"confidence":"High","gaps":["Mechanism of C-terminal morphogenesis function unresolved","Yeast ortholog; mammalian domain roles not directly tested"]},{"year":2002,"claim":"Showed Sec10 function can be tissue- and cargo-specific rather than supporting universal exocytosis.","evidence":"Tissue-specific transgenic RNAi and ecdysone-feeding rescue in Drosophila ring gland","pmids":["12453153"],"confidence":"High","gaps":["Molecular basis of secretory selectivity unknown","Restricted to endocrine secretion phenotype"]},{"year":2011,"claim":"Connected the exocyst to ciliogenesis by identifying its role in ciliary delivery of polycystin-2 and IFT proteins, linking EXOC5 to polycystic-kidney-relevant signaling.","evidence":"shRNA knockdown/overexpression with EM and rescue in MDCK cells, plus co-IP with PKD2/IFT88/IFT20 and zebrafish epistasis with pkd2","pmids":["19297529","21490950"],"confidence":"High","gaps":["Direct vs indirect nature of Sec10-PKD2 interaction not resolved","Vesicle targeting determinants for ciliary cargo undefined"]},{"year":2012,"claim":"Linked the exocyst to early secretory steps by showing Sec10 acts at the rough ER translocon during basolateral protein synthesis.","evidence":"GST pulldown with Sec61β, cell-free translation/translocation assay, and Sec61β phosphorylation analysis","pmids":["23037926"],"confidence":"Medium","gaps":["Functional consequence of Sec61β phosphorylation not established","Single lab, limited mechanistic follow-up"]},{"year":2014,"claim":"Expanded EXOC5 roles to receptor endocytosis, endosomal recycling, and cell migration through distinct effectors.","evidence":"Co-IP with EGFR plus pharmacological dissection of an EGFR-endocytosis-MAPK axis; RNAi epistasis of SEC-10 in C. elegans endosomal tubules with RAB-10; DGKγ-dependent migration assays in MDCK cells","pmids":["25298525","25301900","29326040"],"confidence":"Medium","gaps":["Whether EGFR and DGKγ interactions are direct unresolved","Connection between these activities and the core tethering function unclear"]},{"year":2015,"claim":"Demonstrated tissue-level requirements for EXOC5-mediated trafficking in epithelial barrier formation, polarity, and cell survival.","evidence":"Conditional KO mice and zebrafish/MDCK models showing uroplakin-3 delivery, mitotic spindle orientation, and apoptotic extrusion phenotypes","pmids":["26046524","26040895","26024121"],"confidence":"Medium","gaps":["Molecular link between exocyst and spindle orientation undefined","Cargo specificity for apical uroplakin delivery not mapped"]},{"year":2017,"claim":"Provided the first atomic-level view of Sec10, defining its architecture within the exocyst.","evidence":"2.73 Å X-ray crystal structure of near-full-length zebrafish Sec10","pmids":["28098232"],"confidence":"High","gaps":["Structure of Sec10 within the assembled octamer not resolved","Domain interfaces to partner subunits not directly visualized"]},{"year":2018,"claim":"Established actin-dependence of exocyst-mediated exocytosis and EXOC5 requirement for sensory tissue maintenance.","evidence":"Sec10-formin fusion (For1F) complementation and actin-dependent Sec6 association in Physcomitrella; conditional Exoc5 KO in cochlear hair cells/spiral ganglion neurons","pmids":["29374070","29327200"],"confidence":"Medium","gaps":["Mechanism coupling actin to exocyst tethering in mammals untested","Cell-survival vs trafficking causality in cochlea unresolved"]},{"year":2021,"claim":"Extended EXOC5 trafficking requirement to RPE and photoreceptor maintenance.","evidence":"RPE-specific conditional KO mice and zebrafish exoc5 mutants with ERG, histology, and opsin/RPE65 analysis","pmids":["34064901"],"confidence":"Medium","gaps":["Specific cargo whose mistrafficking drives RPE failure not identified","Single lab"]},{"year":2024,"claim":"Identified a requirement for EXOC5 in folliculogenesis and oocyte developmental competence.","evidence":"Oocyte-specific Zp3-Cre conditional KO mouse with IVF and follicle staging","pmids":["39037927"],"confidence":"Medium","gaps":["Molecular mechanism in oocytes undefined","Trafficking cargo responsible not identified"]},{"year":2025,"claim":"Uncovered an unexpected role for EXOC5 as a negative regulator of antiviral innate immunity via degradation and transcriptional control of JAK-STAT components.","evidence":"Co-IP, site-specific ubiquitination mutagenesis, and myeloid-specific KO mice for STUB1-STAT1 K6-ubiquitination; reporter/promoter assays for NRF2-ATF4-RIG-I suppression","pmids":["40920886","41079927"],"confidence":"High","gaps":["How a secretory scaffold engages cytoplasmic ubiquitin/transcriptional machinery unclear","Relationship to exocyst tethering function unknown"]},{"year":2026,"claim":"Broadened the immunosuppressive role to STING1 autophagic degradation, JAK1 transcriptional control, macrophage migration, and renal fibrosis, defining EXOC5 as a multi-axis innate-immune and tissue-homeostasis regulator.","evidence":"Co-IP and ubiquitination mutagenesis for TRIM56-STING1-SQSTM1; KLF15-JAK1 reporter analysis; exosome/formin1 macrophage migration with pharmacological dissection; proximal tubule KO and HK-2 siRNA for YAP/EMT","pmids":["41968661","41903488","41604889","41781492"],"confidence":"Medium","gaps":["Whether ubiquitin-pathway and transcriptional activities depend on assembled exocyst untested","Direct vs indirect engagement of YAP and KLF15 unresolved"]},{"year":null,"claim":"How EXOC5 partitions between its canonical exocyst-tethering scaffold role and its non-canonical roles in ubiquitin-mediated degradation and transcriptional regulation of immune signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical model linking exocyst assembly to STAT1/STING1/RIG-I regulation","Whether degradation activities require the intact octamer or free EXOC5 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18,19]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,4]}],"complexes":["exocyst"],"partners":["EXOC6","SEC61B","PKD2","IFT88","IFT20","EGFR","STUB1","TRIM56"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00471","full_name":"Exocyst complex component 5","aliases":["Exocyst complex component Sec10","hSec10"],"length_aa":708,"mass_kda":81.9,"function":"Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane","subcellular_location":"Cytoplasm; Midbody","url":"https://www.uniprot.org/uniprotkb/O00471/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EXOC5","classification":"Common Essential","n_dependent_lines":693,"n_total_lines":1208,"dependency_fraction":0.5736754966887417},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EXOC5","total_profiled":1310},"omim":[{"mim_id":"615283","title":"EXOCYST COMPLEX COMPONENT 8; EXOC8","url":"https://www.omim.org/entry/615283"},{"mim_id":"614117","title":"EXOCYST COMPLEX COMPONENT 3-LIKE 1; EXOC3L1","url":"https://www.omim.org/entry/614117"},{"mim_id":"604469","title":"EXOCYST COMPLEX COMPONENT 5; EXOC5","url":"https://www.omim.org/entry/604469"},{"mim_id":"179551","title":"RAS-LIKE PROTOONCOGENE B; RALB","url":"https://www.omim.org/entry/179551"},{"mim_id":"179550","title":"RAS-LIKE PROTOONCOGENE A; RALA","url":"https://www.omim.org/entry/179550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EXOC5"},"hgnc":{"alias_symbol":["SEC10","SEC10P"],"prev_symbol":["SEC10L1"]},"alphafold":{"accession":"O00471","domains":[{"cath_id":"1.20.58","chopping":"561-707","consensus_level":"high","plddt":90.7618,"start":561,"end":707},{"cath_id":"1.20.5","chopping":"39-121","consensus_level":"high","plddt":91.5154,"start":39,"end":121},{"cath_id":"1.20.190","chopping":"377-394_403-547","consensus_level":"high","plddt":84.8871,"start":377,"end":547}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00471","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00471-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00471-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EXOC5","jax_strain_url":"https://www.jax.org/strain/search?query=EXOC5"},"sequence":{"accession":"O00471","fasta_url":"https://rest.uniprot.org/uniprotkb/O00471.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00471/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00471"}},"corpus_meta":[{"pmid":"19297529","id":"PMC_19297529","title":"The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19297529","citation_count":155,"is_preprint":false},{"pmid":"21490950","id":"PMC_21490950","title":"The exocyst protein Sec10 interacts with Polycystin-2 and knockdown causes PKD-phenotypes.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21490950","citation_count":78,"is_preprint":false},{"pmid":"12453153","id":"PMC_12453153","title":"Drosophila sec10 is required for hormone secretion but not general exocytosis or neurotransmission.","date":"2002","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/12453153","citation_count":40,"is_preprint":false},{"pmid":"26046524","id":"PMC_26046524","title":"Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26046524","citation_count":39,"is_preprint":false},{"pmid":"9658167","id":"PMC_9658167","title":"Dominant negative alleles of SEC10 reveal distinct domains involved in secretion and morphogenesis in yeast.","date":"1998","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/9658167","citation_count":37,"is_preprint":false},{"pmid":"9119050","id":"PMC_9119050","title":"Identification and characterization of homologues of the Exocyst component Sec10p.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9119050","citation_count":36,"is_preprint":false},{"pmid":"25301900","id":"PMC_25301900","title":"SEC-10 and RAB-10 coordinate basolateral recycling of clathrin-independent cargo through endosomal tubules in Caenorhabditis elegans.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25301900","citation_count":33,"is_preprint":false},{"pmid":"20053792","id":"PMC_20053792","title":"Exocyst Sec10 protects epithelial barrier integrity and enhances recovery following oxidative stress, by activation of the MAPK pathway.","date":"2010","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20053792","citation_count":25,"is_preprint":false},{"pmid":"26024121","id":"PMC_26024121","title":"Cdc42 and sec10 Are Required for Normal Retinal Development in Zebrafish.","date":"2015","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/26024121","citation_count":24,"is_preprint":false},{"pmid":"25298525","id":"PMC_25298525","title":"Exocyst Sec10 protects renal tubule cells from injury by EGFR/MAPK activation and effects on endocytosis.","date":"2014","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25298525","citation_count":22,"is_preprint":false},{"pmid":"29374070","id":"PMC_29374070","title":"An ancient Sec10-formin fusion provides insights into actin-mediated regulation of exocytosis.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29374070","citation_count":20,"is_preprint":false},{"pmid":"26040895","id":"PMC_26040895","title":"The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity.","date":"2015","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26040895","citation_count":19,"is_preprint":false},{"pmid":"28098232","id":"PMC_28098232","title":"Crystal structure of Sec10, a subunit of the exocyst complex.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28098232","citation_count":18,"is_preprint":false},{"pmid":"29327200","id":"PMC_29327200","title":"Exocyst Complex Member EXOC5 Is Required for Survival of Hair Cells and Spiral Ganglion Neurons and Maintenance of Hearing.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29327200","citation_count":9,"is_preprint":false},{"pmid":"29326040","id":"PMC_29326040","title":"Downregulation of exocyst Sec10 accelerates kidney tubule cell recovery through enhanced cell migration.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29326040","citation_count":7,"is_preprint":false},{"pmid":"23037926","id":"PMC_23037926","title":"Exocyst Sec10 is involved in basolateral protein translation and translocation in the endoplasmic reticulum.","date":"2012","source":"Nephron. Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/23037926","citation_count":7,"is_preprint":false},{"pmid":"34064901","id":"PMC_34064901","title":"Conditional Loss of the Exocyst Component Exoc5 in Retinal Pigment Epithelium (RPE) Results in RPE Dysfunction, Photoreceptor Cell Degeneration, and Decreased Visual Function.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34064901","citation_count":6,"is_preprint":false},{"pmid":"39037927","id":"PMC_39037927","title":"Oocyte-specific EXOC5 expression is required for mouse oogenesis and folliculogenesis.","date":"2024","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/39037927","citation_count":4,"is_preprint":false},{"pmid":"40920886","id":"PMC_40920886","title":"Sec10 suppresses antiviral innate immune response by facilitating STUB1-mediated STAT1 degradation.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/40920886","citation_count":3,"is_preprint":false},{"pmid":"41079927","id":"PMC_41079927","title":"Sec10 negatively regulates antiviral immunity by downregulating NRF2-ATF4-RIG-I axis.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41079927","citation_count":2,"is_preprint":false},{"pmid":"41781492","id":"PMC_41781492","title":"Deficiency of exocyst complex component Exoc5 exacerbates the progression of kidney fibrosis.","date":"2026","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41781492","citation_count":0,"is_preprint":false},{"pmid":"41903488","id":"PMC_41903488","title":"SEC10 suppresses KLF15-mediated transcriptional activation of JAK1 and promotes BoHV-1 replication.","date":"2026","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41903488","citation_count":0,"is_preprint":false},{"pmid":"41604889","id":"PMC_41604889","title":"Myeloid-specific Exoc5 deficiency develops renal inflammation and hypertension.","date":"2026","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/41604889","citation_count":0,"is_preprint":false},{"pmid":"41968661","id":"PMC_41968661","title":"EXOC5/SEC10 attenuates antiviral IFN-I signaling by targeting STING1 for autophagic degradation.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41968661","citation_count":0,"is_preprint":false},{"pmid":"40632529","id":"PMC_40632529","title":"The C-terminal domain of SEC-10 is fundamental for exocyst function, apical organization, and cell morphogenesis in Neurospora crassa.","date":"2025","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/40632529","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14389,"output_tokens":6522,"usd":0.070499,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15420,"output_tokens":4373,"usd":0.093213,"stage2_stop_reason":"end_turn"},"total_usd":0.163712,"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\": 1997,\n      \"finding\": \"Human Sec10p (hSec10p) was identified as a 77-kDa protein component of the mammalian exocyst complex, with broad tissue distribution. Co-transfection of hSec10p and mammalian Sec8p in COS cells demonstrated identical subcellular distribution including peripheral cytoplasmic localization, establishing hSec10p as a mammalian exocyst subunit involved in post-Golgi traffic.\",\n      \"method\": \"Cloning, Northern/Western blot, immunofluorescence co-localization in co-transfected COS cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and expression data from single lab, co-transfection but no co-IP or reconstitution reported in abstract\",\n      \"pmids\": [\"9119050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Sec10p has two functional domains: the N-terminal two-thirds directly interacts with exocyst component Sec15p, and overexpression of this domain displaces full-length Sec10 from the exocyst complex, causing a block in exocytosis and accumulation of secretory vesicles. The C-terminal domain does not interact with other exocyst members and does not cause a secretory defect, but instead is required for morphogenesis (cell elongation), suggesting Sec10p has bifunctional roles in exocytosis and morphogenesis.\",\n      \"method\": \"Dominant-negative mutagenesis, biochemical fractionation, phenotypic analysis in S. cerevisiae\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple domain mutants with distinct phenotypes, biochemical displacement of complex, replicated genetic approach in yeast ortholog\",\n      \"pmids\": [\"9658167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila Sec10 (dSec10) is essential for endocrine (steroid hormone) secretion in the ring gland. Tissue-specific RNAi knockdown showed no essential requirement in nervous system, musculature, gut, or epidermis, and no defects in neuromuscular synapse morphogenesis or neurotransmission. Developmental arrest from dSec10 RNAi was partially rescued by feeding ecdysone, demonstrating a specific role in steroid hormone secretion rather than general exocytosis.\",\n      \"method\": \"Transgenic RNAi knockdown, tissue-specific rescue with ecdysone feeding, neuromuscular synapse morphology and physiology assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment, multiple tissue-specific knockdowns with orthogonal assays, pharmacological rescue\",\n      \"pmids\": [\"12453153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Exocyst protein Sec10 regulates primary ciliogenesis in MDCK renal epithelial cells. shRNA knockdown of Sec10 results in primary cilia containing only basal bodies (no axoneme extension), while Sec10 overexpression increases ciliogenesis. Sec10 knockdown also prevents normal cyst morphogenesis in collagen matrix. Par3 co-localizes with and co-immunoprecipitates with the exocyst, consistent with a role in targeting vesicles for ciliogenesis. Rescue with shRNA-resistant human Sec10 confirmed specificity.\",\n      \"method\": \"shRNA knockdown, stable overexpression, immunofluorescence, scanning and transmission electron microscopy, co-immunoprecipitation, collagen matrix cystogenesis assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, IF, co-IP), genetic rescue, both loss- and gain-of-function in single study\",\n      \"pmids\": [\"19297529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sec10 biochemically interacts with ciliary proteins polycystin-2 (PKD2), IFT88, and IFT20 by co-immunoprecipitation, and co-localizes with polycystin-2 at the primary cilium. Sec10 knockdown in MDCK cells causes loss of flow-generated calcium increases, hyperproliferation, and abnormal MAPK activation. In zebrafish, sec10 morpholino knockdown phenocopies pkd2 knockdown (curly tail, left-right patterning defects, glomerular expansion), and sec10/pkd2 double knockdown shows synergistic genetic interaction, supporting a model where the exocyst is required for ciliary localization of polycystin-2.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, zebrafish morpholino knockdown, genetic epistasis (synergistic interaction), calcium imaging, MAPK activity assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction, genetic epistasis in vivo, multiple orthogonal phenotypic readouts across two model systems\",\n      \"pmids\": [\"21490950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sec10 biochemically interacts with the translocon subunit Sec61β (by GST pulldown), and is preferentially recruited to ER membranes during basolateral (not apical) protein synthesis. In cell-free translation/translocation assays, exocyst depletion enhanced recruitment to ER membranes during basolateral G protein of VSV translation compared to apical hemagglutinin translation. Sec10 overexpression increases Sec61β phosphorylation, suggesting a regulatory role in basolateral protein translocation at the rough ER.\",\n      \"method\": \"GST pulldown, cell-free translation/translocation assay, 32P-orthophosphate labeling and immunoprecipitation\",\n      \"journal\": \"Nephron. Experimental nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro assay and pulldown but single lab, limited mechanistic follow-up reported in abstract\",\n      \"pmids\": [\"23037926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sec10 (exocyst) biochemically interacts with the epidermal growth factor receptor (EGFR) by co-immunoprecipitation. Sec10-overexpressing cells show greater phospho-ERK levels in response to EGF, increased EGFR endocytosis, and are protected from cell injury. Gefitinib (EGFR inhibitor) and Dynasore (dynamin inhibitor) both reduce EGFR endocytosis; inhibition of MAPK reduces EGFR endocytosis, suggesting a feedback loop. Gefitinib reverses the protective effect of Sec10 overexpression, causally linking the Sec10-EGFR-endocytosis-MAPK axis to cellular protection.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibition (gefitinib, U0126, Dynasore), EGFR endocytosis assay, cell injury assay, zebrafish morpholino knockdown\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with pharmacological rescue and in vivo zebrafish validation, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"25298525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In C. elegans intestine, SEC-10 (exocyst subunit) is required for formation of endosomal tubular networks needed for basolateral recycling of clathrin-independent endocytic (CIE) cargoes (hTAC, GLUT1, DAF-4). Depletion of SEC-10 or other exocyst subunits converts tubular endosomes to ring-like structures. Epistasis analysis placed SEC-10 at an intermediate step between early endosomes and recycling endosomes. SEC-10 coordinates with RAB-10 and microtubules to maintain the endosomal tubular network.\",\n      \"method\": \"RNAi depletion, live-cell imaging of endosomal structures, genetic epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis placing SEC-10 in pathway, multiple exocyst subunit depletions, multiple cargo types, C. elegans ortholog\",\n      \"pmids\": [\"25301900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec10 is required for urothelial barrier integrity during development. Conditional knockout of Sec10 in ureteric bud-derived cells (Ksp1.3-Cre) caused decreased uroplakin-3 at the luminal apical surface (by E16.5) and complete absence by E17.5, followed by urothelial degeneration and ureteropelvic junction obstruction. This demonstrates that Sec10-mediated exocytosis is required for apical delivery of uroplakin proteins to establish the urothelial barrier.\",\n      \"method\": \"Conditional knockout mouse (Cre-lox), immunofluorescence for uroplakin-3 localization, histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — first conditional Sec10 KO with mechanistic endpoint (uroplakin trafficking defect) and temporal characterization\",\n      \"pmids\": [\"26046524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec10 and Cdc42 act in the same genetic pathway during retinal development in zebrafish. Sec10 morpholino knockdown causes loss of outer nuclear layer and irregular RPE, with an intracellular melanosome transport defect (retrograde). Sub-optimal co-injection of sec10 and cdc42 morpholinos produced synergistic phenotypes, establishing genetic interaction. Sec10 is required for outer segment development of photoreceptors, likely by trafficking proteins necessary for ciliogenesis.\",\n      \"method\": \"Morpholino knockdown, synergistic genetic interaction analysis, melanosome transport assay, histology, transmission electron microscopy\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by synergy test, multiple readouts, single lab\",\n      \"pmids\": [\"26024121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sec10 knockdown in MDCK cells causes increased basal apoptotic cell extrusion, increased sensitivity to apoptotic triggers, and altered mitotic spindle angles (planar cell polarity defect) during 3D cystogenesis in collagen, without disrupting apico-basal polarity. These phenotypes were rescued by shRNA-resistant human Sec10. Kidney-specific Sec10 KO mice also showed defects in primary cilia assembly and abnormal epithelial cell extrusion in renal tubules.\",\n      \"method\": \"shRNA knockdown, genetic rescue, 3D collagen culture cystogenesis, apoptosis assay, mitotic spindle angle measurement, conditional KO mouse histology\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue confirms specificity, multiple in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"26040895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of near-full-length zebrafish Sec10 was solved at 2.73 Å resolution. The structure consists of tandem antiparallel helix bundles forming a straight rod, consistent with helical core regions of other exocyst subunits, providing the first atomic-level structural details of Sec10.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.73 Å, near-full-length protein, direct structural determination\",\n      \"pmids\": [\"28098232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the moss Physcomitrella patens, For1F encodes a fusion protein of Sec10 (exocyst subunit) and formin (actin nucleation factor). Reduction of For1F or actin filaments inhibits exocytosis. For1F dynamically associates with Sec6 (another exocyst subunit) in an actin-dependent manner. Complementation experiments showed either half alone can rescue loss of For1F, indicating the fusion is not essential but actin filaments are required for exocyst-mediated exocytosis.\",\n      \"method\": \"Genetic complementation, live-cell imaging of protein dynamics, actin disruption, exocytosis assay in Physcomitrella patens\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation and dynamic imaging, but non-mammalian/plant ortholog system; actin-regulation of exocyst is mechanistically informative for Sec10 function\",\n      \"pmids\": [\"29374070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional deletion of Exoc5 (EXOC5) in cochlear hair cells (Gfi1Cre) or otic epithelium (rAAV-iCre) results in apoptosis of hair cells with stereociliary bundle disorganization and apoptotic degeneration of spiral ganglion neurons, demonstrating that Exoc5 is required for survival and maintenance of cochlear hair cells and spiral ganglion neurons.\",\n      \"method\": \"Conditional knockout mice (two independent Cre lines), in utero rAAV delivery, auditory function testing, histology, immunofluorescence\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KO models converge on same cell survival phenotype, single lab\",\n      \"pmids\": [\"29327200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec10 overexpression in MDCK cells inhibits wound healing and ruffle formation, while Sec10 knockdown accelerates both. Sec10-overexpressing cells have higher amounts of diacylglycerol kinase (DGK) gamma at the leading edge, and a DGK inhibitor reverses the inhibition of wound healing and ruffle formation in Sec10-overexpressing cells. This establishes a Sec10-DGKγ regulatory axis in cell migration.\",\n      \"method\": \"Scratch wound assay, immunofluorescence of DGK gamma localization, pharmacological DGK inhibition, shRNA knockdown and stable overexpression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue links DGKγ to Sec10-mediated migration effect, but single lab and single paper\",\n      \"pmids\": [\"29326040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional loss of Exoc5 in retinal pigment epithelium (RPE) of mice causes progressive retinal thinning, abnormal RPE pigmentation, reduced RPE65 levels, reduced c-wave amplitude (dysfunctional RPE), and loss of visual pigments. Exoc5-/- zebrafish show smaller eyes with decreased RPE melanocytes and shorter photoreceptor outer segments with loss of rod and cone opsins, indicating exocyst-mediated trafficking in RPE is required for RPE structure and photoreceptor maintenance.\",\n      \"method\": \"RPE-specific conditional knockout mouse, zebrafish exoc5 mutant, electroretinography (c-wave), histology, immunofluorescence\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent animal models converge on RPE trafficking phenotype, single lab\",\n      \"pmids\": [\"34064901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oocyte-specific deletion of Exoc5 (Zp3-Exoc5-cKO) causes female infertility. The first follicular wave proceeds to the antral stage but produces developmentally incompetent oocytes (failed IVF). Subsequent adult follicular waves do not progress beyond the secondary follicle stage and undergo apoptosis, demonstrating that EXOC5 is required for folliculogenesis and oocyte developmental competence.\",\n      \"method\": \"Oocyte-specific conditional knockout mouse (Zp3-Cre), IVF, histology, follicle staging\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific phenotypic readouts, single lab\",\n      \"pmids\": [\"39037927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec10 negatively regulates antiviral JAK-STAT signaling by interacting with E3 ubiquitin ligase STUB1, promoting STUB1-STAT1 interaction, and accelerating STUB1-mediated proteasomal degradation of STAT1 via K6-linked polyubiquitination at Lys240 and Lys652. Myeloid-specific deletion of Sec10 in mice enhances IFN-I response to viral infection and improves survival.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, proteasome inhibitor treatment, myeloid-specific conditional KO mice, viral infection survival assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific ubiquitination sites identified by mutagenesis, co-IP of complex, in vivo KO confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"40920886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec10 negatively regulates antiviral innate immunity by suppressing RIG-I transcription through inactivation of the NRF2-ATF4 axis. ATF4 binds the RIG-I promoter to promote transcription; NRF2 upregulates ATF4; Sec10 triggers inactivation of NRF2-ATF4 during RNA viral infection, thereby restraining RIG-I expression and IFN-I response. Sec10 deficiency enhances innate immunity and reduces viral load in mice.\",\n      \"method\": \"Transcriptional reporter assays, promoter binding analysis, siRNA knockdown, in vivo Sec10-deficient mice, viral load measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis established, in vivo validation, single lab\",\n      \"pmids\": [\"41079927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EXOC5 facilitates autophagic degradation of STING1 via K63-linked polyubiquitination at Lys224 and Lys338 by E3 ligase TRIM56, which acts as a recognition signal for cargo receptor SQSTM1/p62, thereby attenuating cGAS-STING1-mediated antiviral IFN-I signaling and promoting DNA virus replication. Myeloid-specific Exoc5 deletion in mice improves survival and reduces viral load.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis, autophagy flux assay (bafilomycin A1), siRNA knockdown, myeloid-specific KO mice, viral infection model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific ubiquitination sites by mutagenesis, co-IP of EXOC5-TRIM56-STING1-SQSTM1 complex, autophagic mechanism confirmed, in vivo KO validation\",\n      \"pmids\": [\"41968661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Myeloid-specific Exoc5 deficiency in macrophages reduces exosome release, leading to intracellular accumulation of formin1. This enhances macrophage migration in an actin- and formin1-dependent manner (reversed by actin disruptor and formin1 inhibitor but not Rac1 inhibitor). Enhanced macrophage migration into the kidney causes inflammation and hypertension.\",\n      \"method\": \"Myeloid-specific conditional KO mice (LysM-Cre), exosome quantification, pharmacological inhibition (actin disruptor, formin1 inhibitor, Rac1 inhibitor), macrophage migration assay, adoptive transfer experiment\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of pathway, in vivo transfer experiment, single lab\",\n      \"pmids\": [\"41604889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC10 suppresses JAK1 transcription in a KLF15-dependent manner during BoHV-1 infection. SEC10 downregulates the transcription factor KLF15, which normally promotes JAK1 transcription, thereby establishing a SEC10-KLF15-JAK1 regulatory axis that dampens JAK-STAT-mediated antiviral IFN-I immunity and promotes BoHV-1 replication.\",\n      \"method\": \"siRNA knockdown, transcriptional reporter assays, co-immunoprecipitation, promoter analysis, viral replication assay\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway mechanistically defined by multiple reporters and knockdown, single lab\",\n      \"pmids\": [\"41903488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Exoc5 deficiency in kidney proximal tubule cells increases YAP expression and YAP target genes (CTGF, CYR61), and exacerbates TGF-β-induced epithelial-to-mesenchymal transition and fibrosis following ureteral obstruction. In HK-2 cells, siRNA knockdown of EXOC5 increased both YAP and Pax2 expression, linking Exoc5 to regulation of YAP signaling and tubular cell differentiation.\",\n      \"method\": \"Proximal tubule-specific conditional KO mouse (PEPCK-Cre), unilateral ureteral obstruction model, siRNA knockdown in HK-2 cells, Western blot for YAP/CTGF/CYR61/Pax2\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and in vitro siRNA converge on same pathway, single lab\",\n      \"pmids\": [\"41781492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOC5/Sec10 is a central structural subunit of the heterooctameric exocyst complex that functions as a bifunctional scaffold: its N-terminal domain directly binds Sec15p to maintain exocyst integrity and drive polarized secretory vesicle docking at the plasma membrane, while its C-terminal helical rod domain (visualized by crystal structure) is required for morphogenesis; in mammalian and model organism systems, Sec10 regulates primary ciliogenesis (by mediating ciliary delivery of polycystin-2, IFT88, and IFT20), basolateral protein translocation at the rough ER (via interaction with Sec61β), EGFR endocytosis-dependent MAPK signaling, epithelial barrier maintenance (apical uroplakin delivery), cell migration (through DGKγ and formin1), and innate immune suppression (by promoting STUB1-mediated K6-ubiquitination and proteasomal degradation of STAT1, and TRIM56-mediated K63-ubiquitination and autophagic degradation of STING1).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOC5/Sec10 is a structural subunit of the heterooctameric exocyst complex that drives polarized exocytosis by tethering post-Golgi secretory vesicles for docking at the plasma membrane [#0, #1]. It is a bifunctional scaffold: its N-terminal two-thirds directly binds the exocyst subunit Sec15p to maintain complex integrity and support exocytosis, while its C-terminal helical-rod domain — visualized as tandem antiparallel helix bundles by crystallography — is separately required for morphogenesis [#1, #11]. Through this exocyst-tethering activity EXOC5 governs primary ciliogenesis in renal epithelia, mediating ciliary delivery of polycystin-2 (PKD2), IFT88, and IFT20, with loss of EXOC5 abolishing axoneme extension, flow-induced calcium signaling, and normal cyst morphogenesis [#3, #4]. EXOC5-dependent trafficking is required for apical and basolateral cargo delivery across epithelia, including uroplakin-3 deposition for urothelial barrier formation and CIE-cargo recycling through endosomal tubular networks coordinated with RAB-10 [#7, #8]. EXOC5 supports cell survival and tissue maintenance in cochlear hair cells and spiral ganglion neurons, retinal pigment epithelium and photoreceptors, and developing oocytes, and modulates cell migration through DGKγ and formin1 [#13, #15, #16, #14]. Beyond secretion, EXOC5 is a negative regulator of antiviral type-I interferon signaling: it promotes STUB1-mediated K6-linked polyubiquitination and proteasomal degradation of STAT1, TRIM56-mediated K63-linked polyubiquitination and SQSTM1/p62-dependent autophagic degradation of STING1, and transcriptional suppression of RIG-I and JAK1 [#17, #19, #18, #21]. In the kidney, EXOC5 also restrains YAP signaling and TGF-β-driven epithelial-to-mesenchymal transition and fibrosis [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that a mammalian Sec10 ortholog exists as a bona fide exocyst subunit, extending yeast secretory machinery to human post-Golgi traffic.\",\n      \"evidence\": \"Cloning of human Sec10p with Northern/Western analysis and co-localization with Sec8p in co-transfected COS cells\",\n      \"pmids\": [\"9119050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-localization only, no co-IP or reconstitution of the mammalian complex\", \"Cargo and functional role not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined Sec10 as a bifunctional protein with separable domains, answering how one subunit can serve both exocytosis and morphogenesis.\",\n      \"evidence\": \"Domain-mapping dominant-negative mutants, biochemical fractionation, and phenotypic analysis in S. cerevisiae showing N-terminal Sec15p binding and C-terminal morphogenesis role\",\n      \"pmids\": [\"9658167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of C-terminal morphogenesis function unresolved\", \"Yeast ortholog; mammalian domain roles not directly tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed Sec10 function can be tissue- and cargo-specific rather than supporting universal exocytosis.\",\n      \"evidence\": \"Tissue-specific transgenic RNAi and ecdysone-feeding rescue in Drosophila ring gland\",\n      \"pmids\": [\"12453153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of secretory selectivity unknown\", \"Restricted to endocrine secretion phenotype\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected the exocyst to ciliogenesis by identifying its role in ciliary delivery of polycystin-2 and IFT proteins, linking EXOC5 to polycystic-kidney-relevant signaling.\",\n      \"evidence\": \"shRNA knockdown/overexpression with EM and rescue in MDCK cells, plus co-IP with PKD2/IFT88/IFT20 and zebrafish epistasis with pkd2\",\n      \"pmids\": [\"19297529\", \"21490950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of Sec10-PKD2 interaction not resolved\", \"Vesicle targeting determinants for ciliary cargo undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked the exocyst to early secretory steps by showing Sec10 acts at the rough ER translocon during basolateral protein synthesis.\",\n      \"evidence\": \"GST pulldown with Sec61β, cell-free translation/translocation assay, and Sec61β phosphorylation analysis\",\n      \"pmids\": [\"23037926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Sec61β phosphorylation not established\", \"Single lab, limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded EXOC5 roles to receptor endocytosis, endosomal recycling, and cell migration through distinct effectors.\",\n      \"evidence\": \"Co-IP with EGFR plus pharmacological dissection of an EGFR-endocytosis-MAPK axis; RNAi epistasis of SEC-10 in C. elegans endosomal tubules with RAB-10; DGKγ-dependent migration assays in MDCK cells\",\n      \"pmids\": [\"25298525\", \"25301900\", \"29326040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EGFR and DGKγ interactions are direct unresolved\", \"Connection between these activities and the core tethering function unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated tissue-level requirements for EXOC5-mediated trafficking in epithelial barrier formation, polarity, and cell survival.\",\n      \"evidence\": \"Conditional KO mice and zebrafish/MDCK models showing uroplakin-3 delivery, mitotic spindle orientation, and apoptotic extrusion phenotypes\",\n      \"pmids\": [\"26046524\", \"26040895\", \"26024121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between exocyst and spindle orientation undefined\", \"Cargo specificity for apical uroplakin delivery not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the first atomic-level view of Sec10, defining its architecture within the exocyst.\",\n      \"evidence\": \"2.73 Å X-ray crystal structure of near-full-length zebrafish Sec10\",\n      \"pmids\": [\"28098232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of Sec10 within the assembled octamer not resolved\", \"Domain interfaces to partner subunits not directly visualized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established actin-dependence of exocyst-mediated exocytosis and EXOC5 requirement for sensory tissue maintenance.\",\n      \"evidence\": \"Sec10-formin fusion (For1F) complementation and actin-dependent Sec6 association in Physcomitrella; conditional Exoc5 KO in cochlear hair cells/spiral ganglion neurons\",\n      \"pmids\": [\"29374070\", \"29327200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling actin to exocyst tethering in mammals untested\", \"Cell-survival vs trafficking causality in cochlea unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended EXOC5 trafficking requirement to RPE and photoreceptor maintenance.\",\n      \"evidence\": \"RPE-specific conditional KO mice and zebrafish exoc5 mutants with ERG, histology, and opsin/RPE65 analysis\",\n      \"pmids\": [\"34064901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo whose mistrafficking drives RPE failure not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a requirement for EXOC5 in folliculogenesis and oocyte developmental competence.\",\n      \"evidence\": \"Oocyte-specific Zp3-Cre conditional KO mouse with IVF and follicle staging\",\n      \"pmids\": [\"39037927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism in oocytes undefined\", \"Trafficking cargo responsible not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered an unexpected role for EXOC5 as a negative regulator of antiviral innate immunity via degradation and transcriptional control of JAK-STAT components.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination mutagenesis, and myeloid-specific KO mice for STUB1-STAT1 K6-ubiquitination; reporter/promoter assays for NRF2-ATF4-RIG-I suppression\",\n      \"pmids\": [\"40920886\", \"41079927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a secretory scaffold engages cytoplasmic ubiquitin/transcriptional machinery unclear\", \"Relationship to exocyst tethering function unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Broadened the immunosuppressive role to STING1 autophagic degradation, JAK1 transcriptional control, macrophage migration, and renal fibrosis, defining EXOC5 as a multi-axis innate-immune and tissue-homeostasis regulator.\",\n      \"evidence\": \"Co-IP and ubiquitination mutagenesis for TRIM56-STING1-SQSTM1; KLF15-JAK1 reporter analysis; exosome/formin1 macrophage migration with pharmacological dissection; proximal tubule KO and HK-2 siRNA for YAP/EMT\",\n      \"pmids\": [\"41968661\", \"41903488\", \"41604889\", \"41781492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ubiquitin-pathway and transcriptional activities depend on assembled exocyst untested\", \"Direct vs indirect engagement of YAP and KLF15 unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EXOC5 partitions between its canonical exocyst-tethering scaffold role and its non-canonical roles in ubiquitin-mediated degradation and transcriptional regulation of immune signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical model linking exocyst assembly to STAT1/STING1/RIG-I regulation\", \"Whether degradation activities require the intact octamer or free EXOC5 is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18, 19]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"EXOC6\", \"SEC61B\", \"PKD2\", \"IFT88\", \"IFT20\", \"EGFR\", \"STUB1\", \"TRIM56\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}