Affinage

EXOC8

Exocyst complex component 8 · UniProt Q8IYI6

Round 2 corrected
Length
725 aa
Mass
81.8 kDa
Annotated
2026-04-28
45 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXOC8 (Exo84) is an essential subunit of the octameric exocyst complex that tethers secretory vesicles to the plasma membrane, functioning as a direct effector of Ral GTPases to regulate exocyst assembly, polarized secretion, autophagy, and insulin-stimulated GLUT4 trafficking. Its Ral-binding domain adopts a PH-domain fold that competitively engages active RalA/RalB with Sec5, enabling Ral-dependent toggling between exocyst subcomplexes; upon nutrient starvation, RalB–Exo84 interaction recruits ULK1 and Beclin1–VPS34 autophagy initiation complexes to nascent autophagosomes (PMID:15920473, PMID:21241894). Phosphorylation of EXOC8 by Cdk1 during mitosis and G1/S disrupts exocyst assembly to arrest secretory growth, while TBK1 phosphorylation downstream of insulin–RalA signaling modulates GLUT4 vesicle docking in adipocytes (PMID:23836930, PMID:31171719, PMID:28325821). Loss-of-function variants in EXOC8 cause a recessively inherited neurodevelopmental disorder with brain atrophy, seizures, and microcephaly (PMID:32103185).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 Medium

    Identification of an 84-kDa protein as a novel mammalian exocyst subunit established EXOC8 as an integral component of the secretory vesicle tethering machinery.

    Evidence cDNA cloning and immunoprecipitation of mammalian exocyst complex

    PMID:9405631

    Open questions at the time
    • Mammalian-specific function of Exo84 vs. other subunits not defined
    • no loss-of-function data in mammalian cells at this stage
  2. 1999 High

    Genetic depletion and biochemical reconstitution in yeast demonstrated that Exo84p is essential for post-Golgi vesicle targeting and that its assembly into the exocyst depends on Sec5p/Sec10p, establishing its position in the complex hierarchy.

    Evidence Yeast depletion strains, invertase secretion assay, co-IP, velocity sedimentation, EM

    PMID:10438536

    Open questions at the time
    • Mammalian essentiality not yet tested
    • direct membrane-binding properties unknown
  3. 2003 High

    Discovery that Exo84 is a direct Ral GTPase effector—alongside Sec5—revealed that Ral signaling assembles distinct exocyst subcomplexes from vesicular and plasma-membrane pools, answering how upstream signaling controls exocyst assembly.

    Evidence Co-IP, GST pulldown, dominant-negative constructs, subcellular fractionation in mammalian cells

    PMID:14525976

    Open questions at the time
    • Structural basis of Ral–Exo84 interaction unknown
    • relative contributions of Sec5 vs Exo84 to exocytosis unclear
  4. 2005 High

    Crystal structures of the Exo84 Ral-binding domain (PH-fold) in complex with RalA, and of yeast Exo84p helical-bundle domains, provided the atomic basis for competitive RalA engagement with Sec5 and revealed a conserved helical-rod architecture across exocyst subunits.

    Evidence X-ray crystallography (human RBD–RalA complex; yeast C-terminal domains at 2.85 Å), mutagenesis binding studies

    PMID:15920473 PMID:16249794

    Open questions at the time
    • Full-length Exo84 structure not available
    • how competitive Ral binding switches exocyst configuration in vivo undetermined
  5. 2005 High

    Systematic epistasis in yeast showed that Exo84p is required for polarized localization of Sec10p, Sec15p, and Exo70p and for their assembly into the holocomplex, while Exo84p localization itself depends on actin and pre-Golgi traffic, establishing Exo84 as an early-acting assembly scaffold.

    Evidence Temperature-sensitive mutants, co-IP, fluorescence microscopy, cargo trafficking assays in S. cerevisiae

    PMID:15788396

    Open questions at the time
    • Mammalian Exo84 scaffolding hierarchy not tested
    • mechanism of actin-dependent Exo84 recruitment unknown
  6. 2007 High

    Drosophila genetic studies revealed that Exo84 is essential for epithelial apical identity by trafficking Crumbs to the apical surface and maintaining adherens junctions, extending exocyst function from bulk secretion to cell polarity.

    Evidence Drosophila loss-of-function mutants, immunofluorescence, epistasis with dlg/lgl

    PMID:17698923

    Open questions at the time
    • Mammalian epithelial polarity role not directly shown
    • cargo specificity mechanism for Crumbs vs other cargoes unknown
  7. 2011 High

    Demonstration that RalB–Exo84 interaction nucleates ULK1 and Beclin1–VPS34 complexes on nascent autophagosomes during starvation established a non-canonical role for Exo84 as an autophagy scaffold distinct from its exocytic function.

    Evidence RNAi, co-IP, immunofluorescence, autophagy flux assays, dominant-negative constructs in mammalian cells

    PMID:21241894

    Open questions at the time
    • Structural basis of Exo84–ULK1/Beclin1 interaction unknown
    • whether autophagy and exocytosis roles are mutually exclusive in real time undetermined
  8. 2013 High

    Cdk1 phosphorylation of Exo84 during mitosis was shown to disrupt exocyst assembly and inhibit exocytosis, providing a direct molecular mechanism coupling cell-cycle progression to growth arrest.

    Evidence In vitro Cdk1 kinase assay, phosphosite mutagenesis, co-IP, exocytosis assays in yeast

    PMID:23836930

    Open questions at the time
    • Phosphorylation sites in mammalian EXOC8 and their cell-cycle regulation not mapped
    • phosphatase responsible for dephosphorylation unknown
  9. 2017 High

    TBK1 phosphorylation of EXOC8 downstream of insulin–RalA signaling was found to reduce Exo84–RalA affinity and regulate GLUT4 vesicle docking/fusion cycles in adipocytes, linking Exo84 phosphoregulation to metabolic physiology.

    Evidence In vitro kinase assay, adipocyte-specific TBK1 KO, phosphomimetic/phosphodeficient mutagenesis, glucose uptake assays

    PMID:28325821

    Open questions at the time
    • Other kinases that may phosphorylate Exo84 in adipocytes unknown
    • whether TBK1-Exo84 axis operates in non-adipocyte insulin target tissues untested
  10. 2019 High

    Extension of Cdk1 phosphoregulation to late G1 phase showed that Exo84 phosphorylation coordinates exocyst disassembly not only in mitosis but also at G1/S, broadening the cell-cycle window of secretory growth control.

    Evidence Cdk1 kinase assay, phosphomutant yeast strains, secretion assays, conditional cdc mutants

    PMID:31171719

    Open questions at the time
    • Whether G1/S phosphorylation is conserved in mammalian cells unknown
    • interplay between Cdk1 and TBK1 phosphorylation sites not explored
  11. 2020 Medium

    Human genetic studies linked biallelic loss-of-function EXOC8 variants to a neurodevelopmental disorder with brain atrophy and seizures, establishing that EXOC8 is non-redundant for cerebral cortex development.

    Evidence Homozygosity mapping, exome sequencing, Sanger validation, zebrafish model

    PMID:32103185

    Open questions at the time
    • Cellular mechanism (neural progenitor proliferation vs. migration vs. survival) not demonstrated for EXOC8 specifically
    • genotype–phenotype spectrum with hypomorphic alleles unexplored
    • rescue experiments in patient cells not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of Exo84's dual scaffolding roles in exocytosis versus autophagy, how multiple phosphorylation inputs (Cdk1, TBK1, and potentially others) are integrated on the same subunit, and the precise neural cell types and trafficking cargoes disrupted in EXOC8-associated neurological disease.
  • Full-length Exo84 structure in the context of the assembled exocyst lacking
  • no conditional mammalian neural knockout to dissect developmental timing
  • systematic phosphoproteomics of EXOC8 across tissues not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1500931 Cell-Cell communication 1 R-HSA-9612973 Autophagy 1
Partners
EXOC2EXOC3EXOC7RALARALBTBK1ULK1VPS34
Complex memberships
Exocyst complex (Sec6/8 complex)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The mammalian exocyst complex contains an 84-kDa subunit (later designated EXOC8/Exo84) as a novel protein component, identified by characterization of cDNAs encoding mammalian exocyst subunits. cDNA cloning, immunoprecipitation, Western blot Proceedings of the National Academy of Sciences of the United States of America Medium 9405631
1998 The mammalian brain sec6/8 (exocyst) complex, which contains the 84-kDa subunit (EXOC8), co-immunoprecipitates with septin filaments, suggesting a functional interaction between the exocyst and septin complexes at sites of membrane addition in neurons. Co-immunoprecipitation, electron microscopy Neuron Medium 9655500
1999 Yeast Exo84p (ortholog of EXOC8) is an essential exocyst subunit required for post-Golgi secretory vesicle targeting to the plasma membrane; it localizes to sites of polarized secretion (bud tip), co-immunoprecipitates with other exocyst components, and its assembly into the exocyst complex requires Sec5p and Sec10p. Genetic depletion, invertase secretion assay, electron microscopy, co-immunoprecipitation, velocity gradient sedimentation, two-hybrid assay, fluorescence microscopy The Journal of biological chemistry High 10438536
2001 Yeast Exo84p (ortholog of EXOC8) physically interacts with the U1 snRNP component Snp1p and is involved in pre-mRNA splicing; a temperature-sensitive exo84 mutation causes increased pre-mRNA:mRNA ratios and defects in in vitro splicing and prespliceosome formation, revealing an unexpected link between the exocyst and the spliceosome. Two-hybrid assay, co-immunoprecipitation, temperature-sensitive mutant analysis, in vitro splicing assay, Northern blot The Journal of biological chemistry Medium 11425851
2001 The mammalian brain exocyst complex (including the 84-kDa EXOC8 subunit) binds active (GTP-bound) RalA in a GTP-dependent manner in nerve terminals, identifying the exocyst as an effector of neuronal RalA signaling. GTP-dependent pulldown, MALDI-TOF mass spectrometry, co-immunoprecipitation, Western blot The Journal of biological chemistry Medium 11406615
2003 Exo84 (EXOC8) is a direct target of activated Ral GTPases in mammalian cells; Ral GTPases regulate exocyst assembly through dual interactions with both Sec5 and Exo84, and mammalian exocyst components exist as distinct subcomplexes on vesicles and the plasma membrane that are assembled by Ral signaling. Co-immunoprecipitation, GST pulldown, dominant-negative constructs, subcellular fractionation The Journal of biological chemistry High 14525976
2005 Crystal structure of the Ral-binding domain (RBD) of Exo84 in complex with active RalA reveals that the Exo84 RBD adopts a pleckstrin homology (PH) domain fold and that RalA engages Exo84 via both switch regions; Exo84 and Sec5 competitively bind active RalA, indicating a regulatory mechanism for Sec6/8 complex assembly. X-ray crystallography (crystal structure), mutagenesis binding studies, biochemical competition assays The EMBO journal High 15920473
2005 Crystal structures of yeast Exo84p C-terminal domains reveal a long helical-bundle rod architecture (80 Å) with the same fold as the Exo70p N-terminus, suggesting exocyst subunits are composed of helical modules strung into rods, a conserved structural motif across the complex. X-ray crystallography (2.85 Å resolution), structural comparison Nature structural & molecular biology High 16249794
2005 Yeast Exo84p (ortholog of EXOC8) plays a critical role in exocyst complex assembly: several exocyst members (Sec10p, Sec15p, Exo70p) require Exo84p for their polarized localization and for their assembly into the complex, while Exo84p localization itself depends on pre-Golgi trafficking and polarized actin but not on other exocyst subunits. Temperature-sensitive mutant generation, electron microscopy, fluorescence microscopy, co-immunoprecipitation, cargo trafficking assays The Journal of biological chemistry High 15788396
2007 Drosophila Exo84 (ortholog of EXOC8) is essential for epithelial apical identity: it is required for apical localization of the Crumbs transmembrane protein, and loss of Exo84 leads to mislocalization of adherens junction proteins, defects in apical cuticle secretion, and accumulation of apical proteins in an expanded recycling endosome. Genetic loss-of-function (mutant analysis), immunofluorescence microscopy, epistasis with dlg/lgl mutants Journal of cell science High 17698923
2011 RalB and its effector Exo84 (EXOC8) are required for nutrient starvation-induced autophagosome biogenesis in mammalian cells; RalB activation on nascent autophagosomes drives assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst through direct binding to Exo84, enabling isolation membrane formation. RNAi knockdown, co-immunoprecipitation, immunofluorescence, autophagy flux assays, dominant-negative constructs Cell High 21241894
2012 C. elegans exoc-8 (EXOC8 ortholog) mutants display pleiotropic behavior defects resembling cilia mutants and show functional links to RAB-10-regulated endosomal trafficking; exoc-8 and exoc-7;exoc-8 double mutations cause enlarged RAB-10 RNAi-induced endocytic vacuoles and upregulation of RAB-10 expression in intestinal epithelial cells. C. elegans genetic mutant analysis, targeted RNAi screen, fluorescence microscopy, endocytic marker accumulation assays PloS one Medium 22389680
2012 RalA effectors Sec5 and Exo84 (EXOC8) mediate distinct aspects of cell polarization: RalA-Exocyst interactions are directly required for migration and invasion of prostate cancer cells, and blocking RalA-Exocyst binding causes morphological changes and defects in single and coordinated cell migration. Dominant-negative constructs, cell migration assays, invasion assays, morphological analysis PloS one Medium 22761837
2013 Mitotic phosphorylation of yeast Exo84p (EXOC8 ortholog) by Cdk1-Clb2 disrupts exocyst complex assembly, thereby inhibiting exocytosis and cell surface expansion during the metaphase-anaphase transition, providing a molecular mechanism for growth arrest during mitosis. CDK kinase assay, phosphorylation site mutagenesis, co-immunoprecipitation, exocytosis assays, fluorescence microscopy, conditional mutants The Journal of cell biology High 23836930
2013 The exocyst complex (including Exo84/EXOC8) interacts with endosomal WASH complex on MT1-MMP-containing late endosomes in breast carcinoma cells; this interaction is required for exocytic delivery of MT1-MMP at invadopodia to enable matrix degradation and tumor cell invasion. Co-immunoprecipitation, RNAi knockdown, live-cell imaging, matrix degradation assays, proximity ligation assay The Journal of cell biology Medium 24344185
2014 In Candida albicans, phosphorylation of CaExo84 (EXOC8 ortholog) by Cdk1-Hgc1 promotes hyphal extension by altering its affinity for phosphatidylserine, enabling recycling at the plasma membrane without disrupting its localization — a mechanistically distinct outcome from yeast Exo84 phosphorylation, demonstrating functional divergence of Cdk1 regulation of this conserved exocyst subunit. Phosphorylation site mutagenesis, CDK assay, fluorescence microscopy, phosphatidylserine binding assay, genetic analysis Molecular biology of the cell Medium 24501427
2016 The exocyst complex, including EXOC8, is identified as a component of the ciliary protein landscape through affinity proteomics of 217 tagged ciliary proteins, and sub-complexes of the exocyst are biochemically validated, linking exocyst function to ciliogenesis. Affinity proteomics, AP-MS, biochemical validation of sub-complexes, genetic variant analysis in ciliary disease patients Nature communications Medium 27173435
2017 TBK1 directly phosphorylates EXOC8 (Exo84) upon RalA activation by insulin in adipocytes; phosphorylation reduces Exo84's affinity for RalA, enabling its release from the exocyst complex, which is required for proper engagement and disengagement of GLUT4 vesicles at the plasma membrane; both phosphorylation-mimicking and non-phosphorylatable Exo84 mutants block insulin-stimulated GLUT4 translocation. In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, adipocyte-specific TBK1 knockout, glucose uptake assays, phosphomimetic/phosphodeficient mutagenesis, dominant-negative TBK1 Science signaling High 28325821
2019 Yeast Exo84p (EXOC8 ortholog) is phosphorylated by Cdk1 in late G1 phase (in addition to mitosis), and this phosphorylation impairs exocyst complex assembly, exocytic secretion, and cell growth, contributing to coordination of growth arrest at the G1/S transition. CDK kinase assay, immunoprecipitation, phosphodeficient/phosphomimetic exo84 mutants, secretion assays, fluorescence microscopy, conditional cdc mutants The Journal of biological chemistry High 31171719
2020 Loss-of-function variants in EXOC8 in humans cause a recessively inherited neurodevelopmental disorder characterized by brain atrophy, seizures, developmental delay, and in severe cases microcephaly, establishing an essential role for EXOC8 in human cerebral cortex development. Homozygosity mapping, exome sequencing, Sanger sequencing, zebrafish exoc7 knockout model Genetics in medicine Medium 32103185
2025 Active Merlin (NF2 tumor suppressor) competitively inhibits RalB binding to its exocyst effectors Sec5 and Exo84 (EXOC8), and regulates the kinetics of exocytosis in a RalB-dependent manner; proximity biotinylation and direct binding assays identified RalA and RalB as high-affinity PIP2-dependent Merlin binding proteins. Proximity biotinylation (BioID), direct binding assays, co-localization, competitive binding assays, exocytosis kinetics assays bioRxivpreprint Medium bio_10.1101_2025.06.13.659557

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1998 Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments. Neuron 296 9655500
2003 The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 282 12687004
2014 TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. Developmental cell 276 25127057
2012 Exorcising the exocyst complex. Traffic (Copenhagen, Denmark) 275 22420621
2011 RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 256 21241894
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2003 Ral GTPases regulate exocyst assembly through dual subunit interactions. The Journal of biological chemistry 184 14525976
1999 Exo84p is an exocyst protein essential for secretion. The Journal of biological chemistry 160 10438536
1997 Subunit structure of the mammalian exocyst complex. Proceedings of the National Academy of Sciences of the United States of America 155 9405631
2013 Endosomal WASH and exocyst complexes control exocytosis of MT1-MMP at invadopodia. The Journal of cell biology 150 24344185
2006 The DNA sequence and biological annotation of human chromosome 1. Nature 144 16710414
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 122 15920473
2005 The structures of exocyst subunit Exo70p and the Exo84p C-terminal domains reveal a common motif. Nature structural & molecular biology 119 16249794
2001 The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene. The Journal of biological chemistry 119 11406615
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2007 The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. Journal of cell science 100 17698923
2005 The critical role of Exo84p in the organization and polarized localization of the exocyst complex. The Journal of biological chemistry 37 15788396
2017 Phosphorylation of the exocyst protein Exo84 by TBK1 promotes insulin-stimulated GLUT4 trafficking. Science signaling 31 28325821
2013 Mitotic phosphorylation of Exo84 disrupts exocyst assembly and arrests cell growth. The Journal of cell biology 29 23836930
2014 In Candida albicans, phosphorylation of Exo84 by Cdk1-Hgc1 is necessary for efficient hyphal extension. Molecular biology of the cell 27 24501427
2001 New roles for the Snp1 and Exo84 proteins in yeast pre-mRNA splicing. The Journal of biological chemistry 25 11425851
2020 Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival. Genetics in medicine : official journal of the American College of Medical Genetics 23 32103185
2012 Sec5 and Exo84 mediate distinct aspects of RalA-dependent cell polarization. PloS one 15 22761837
2012 Exocyst subunits Exo70 and Exo84 cooperate with small GTPases to regulate behavior and endocytic trafficking in C. elegans. PloS one 14 22389680
2022 A novel nonsense variant in EXOC8 underlies a neurodevelopmental disorder. Neurogenetics 6 35460391
2019 Cyclin-dependent kinase-mediated phosphorylation of the exocyst subunit Exo84 in late G1 phase suppresses exocytic secretion and cell growth in yeast. The Journal of biological chemistry 6 31171719
2025 EXOC8 of Epinephelus coioides involved in SGIV infection via innate immunity and apoptosis. Developmental and comparative immunology 0 40189122