Affinage

EXOC8

Exocyst complex component 8 · UniProt Q8IYI6

Length
725 aa
Mass
81.8 kDa
Annotated
2026-06-09
15 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EXOC8 (Exo84) is an essential subunit of the octameric exocyst complex that tethers and docks post-Golgi secretory vesicles at sites of polarized secretion on the plasma membrane (PMID:10438536, PMID:15788396). It is a structural organizing hub of the complex: its C-terminal domains form an ~80 Å alpha-helical rod fold structurally homologous to Exo70, and Exo84 incorporation is required for assembly of Sec10, Sec15, and Exo70 into the holocomplex, while its own assembly depends on Sec5 and Sec10 (PMID:16249794, PMID:15788396, PMID:10438536). Through a pleckstrin-homology domain fold, Exo84 binds active RalA/RalB GTPases across both switch regions in competition with Sec5, providing a switch by which Ral signaling differentially controls exocyst assembly and vesicle tethering (PMID:15920473, PMID:28325821). Exocyst function through Exo84 is gated by phosphorylation: Cdk1/Clb2 directly phosphorylates Exo84 in both late G1 and mitosis to disrupt complex assembly, inhibit exocytosis, and arrest cell-surface expansion (PMID:23836930, PMID:31171719), and in mammalian adipocytes TBK1 phosphorylates Exo84 downstream of insulin-stimulated RalA activation, lowering its RalA affinity to release it from the complex and drive GLUT4 vesicle fusion (PMID:28325821). Beyond canonical secretion, EXOC8 contributes to apical epithelial polarity and recycling-endosome trafficking in metazoan models (PMID:17698923, PMID:22389680).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established EXOC8/Exo84 as a bona fide, essential exocyst subunit needed for vesicle targeting and docking, answering whether it physically belongs to the secretion machinery.

    Evidence Co-IP, velocity gradient co-sedimentation, two-hybrid, invertase secretion assay, EM and localization in yeast

    PMID:10438536

    Open questions at the time
    • Did not define Exo84's molecular role in tethering beyond complex membership
    • No structural basis for subunit interactions
  2. 2005 High

    Defined the structural and assembly logic of Exo84, showing a conserved alpha-helical rod fold shared with Exo70 and a reciprocal assembly dependency that makes Exo84 a core organizer of the complex.

    Evidence X-ray crystallography of Exo84 and Exo70 C-terminal domains plus ts-mutant exocyst composition analysis in yeast

    PMID:15788396 PMID:16249794

    Open questions at the time
    • Full octameric architecture not resolved
    • Mechanism by which Exo84 nucleates Sec10/Sec15/Exo70 incorporation not detailed
  3. 2005 High

    Revealed how Ral GTPases regulate the exocyst, showing Exo84 binds active RalA through a PH fold in direct competition with Sec5.

    Evidence Crystal structure of RBD-Exo84/RalA at 2.0 Å with mutagenesis and binding assays

    PMID:15920473

    Open questions at the time
    • Functional consequence of Exo84-vs-Sec5 competition for vesicle tethering not established in this study
    • RalB binding not addressed
  4. 2001 Medium

    Proposed a non-canonical nuclear role linking Exo84 to U1 snRNP and pre-mRNA splicing, raising the question of moonlighting functions.

    Evidence Two-hybrid, co-IP with Snp1p, in vivo pre-mRNA accumulation and in vitro splicing assays in yeast

    PMID:11425851

    Open questions at the time
    • Splicing defect could be indirect/secondary to ts-allele effects
    • Not connected to the exocyst's membrane function
    • No mammalian confirmation
  5. 2007 Medium

    Extended EXOC8 function to metazoan epithelial polarity, showing it is required for apical localization of polarity determinants and apical secretion.

    Evidence Drosophila exo84 mutant analysis, immunofluorescence, genetic epistasis with dlg/lgl

    PMID:17698923

    Open questions at the time
    • Direct molecular partners in the apical pathway not defined
    • Single-organism, single-lab finding
  6. 2012 Medium

    Linked EXOC8 to RAB-10-dependent endosomal trafficking, broadening its role beyond plasma-membrane secretion to recycling-endosome dynamics.

    Evidence C. elegans exoc-8 loss-of-function with rab-10 RNAi, endocytic marker accumulation and small-GTPase epistasis screen

    PMID:22389680

    Open questions at the time
    • Direct EXOC8-RAB-10 interaction not shown
    • Mechanism of endosome size control unresolved
  7. 2013 High

    Identified cell-cycle control of the exocyst via direct Cdk1/Clb2 phosphorylation of Exo84 in mitosis that disrupts assembly and halts surface expansion.

    Evidence CDK kinase assay, exocytosis readout and phospho-site mutants in budding yeast

    PMID:23836930

    Open questions at the time
    • Phospho-acceptor residues' structural effect on assembly not detailed
    • Conservation in mammals untested
  8. 2014 Medium

    Showed phosphoregulation of Exo84 is rewired across species, with Candida Cdk1 phosphorylation reducing phosphatidylserine affinity to sustain hyphal growth rather than disrupting assembly.

    Evidence CDK assay, lipid-binding assay, phosphomutant localization in C. albicans

    PMID:24501427

    Open questions at the time
    • Lipid-binding domain mapped indirectly
    • Single-lab, single-organism
  9. 2017 High

    Established a mammalian signaling axis in which TBK1 phosphorylates EXOC8 downstream of insulin/RalA to release it from the exocyst and enable GLUT4 vesicle fusion, requiring dynamic phosphocycling.

    Evidence In vitro kinase assay, TBK1 knockdown/KO/inhibition in adipocytes, RalA binding assay, phosphomutants, GLUT4 translocation and glucose uptake assays

    PMID:28325821

    Open questions at the time
    • Phosphatase that reverses the modification not identified
    • Structural basis of reduced RalA affinity not resolved
  10. 2019 Medium

    Demonstrated Cdk1 phosphorylation of Exo84 also acts at the G1/S transition, generalizing exocyst phosphoregulation across multiple cell-cycle stages.

    Evidence CDK assay, exocytic secretion assay, conditional cdc mutants and phosphomutants in yeast

    PMID:31171719

    Open questions at the time
    • Overlap/distinction with mitotic phospho-sites not fully resolved
    • Mammalian relevance untested
  11. 2025 Low

    Proposed that Merlin/NF2 competitively inhibits RalB binding to Sec5 and Exo84 to tune exocytosis kinetics, implicating EXOC8 in tumor-suppressor-controlled secretion.

    Evidence BioID proximity biotinylation, competitive binding assays and exocytosis kinetics (preprint)

    Open questions at the time
    • Preprint, single lab
    • Exo84-specific mechanistic detail limited
    • Functional consequence in tumor context not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple kinase inputs (Cdk1, TBK1) and Ral/Merlin binding states are integrated on EXOC8 to time exocyst assembly and disassembly in mammalian cells remains unresolved.
  • No phosphatase identified for any Exo84 phospho-site
  • No structure of the full mammalian exocyst showing Exo84 in context
  • Integration of cell-cycle and signaling phospho-inputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 1 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2
Partners
CDK1NF2RALARALBSEC10SEC5SNP1TBK1
Complex memberships
exocyst

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Exo84p (EXOC8) is an essential component of the yeast exocyst complex required for secretory vesicle targeting and docking at the plasma membrane; depletion causes invertase secretion defects and vesicle accumulation. Exo84p co-immunoprecipitates with other exocyst components, co-sediments with the exocyst complex in velocity gradients, and its assembly into the complex requires Sec5p and Sec10p. Exo84p interacts with Sec5p and Sec10p by two-hybrid assay, and overexpression selectively suppresses a sec5 temperature-sensitive mutant. Exo84p localizes to the bud tip/mother-daughter connection (sites of polarized secretion) and is mislocalized in a sec5 mutant. Co-immunoprecipitation, velocity gradient sedimentation, two-hybrid assay, invertase secretion assay, electron microscopy, fluorescence microscopy, genetic suppression The Journal of biological chemistry High 10438536
2005 The Ral-binding domain of Exo84 adopts a pleckstrin homology domain fold and binds active RalA through an extended interface involving both switch regions. Key residues in Exo84 and RalA determine binding specificity. Exo84 and Sec5 competitively bind to active RalA, establishing a mechanism by which Ral GTPases can differentially regulate exocyst assembly. Crystal structure of RBD-Exo84/RalA complex at 2.0 Å, mutagenesis, biochemical binding assays The EMBO journal High 15920473
2005 The C-terminal domains of Exo84p form an 80 Å-long rod with an alpha-helical bundle fold that is structurally homologous to the N-terminal fold of Exo70p, revealing a common structural motif shared among exocyst subunits. X-ray crystallography (Exo84p C-terminal domains at 2.85 Å; Exo70p at 2.0 Å), structural comparison Nature structural & molecular biology High 16249794
2005 Exo84p is specifically involved in post-Golgi secretion and plays a critical role in exocyst complex assembly and polarized targeting. Pre-Golgi trafficking and polarized actin organization are required for Exo84p localization, but no single exocyst protein controls Exo84p polarization. Conversely, assembly of Sec10p, Sec15p, and Exo70p into the exocyst complex requires Exo84p. Temperature-sensitive yeast exo84 mutant analysis, electron microscopy, cargo traffic assays, fluorescence microscopy of exocyst localization, biochemical fractionation of exocyst composition The Journal of biological chemistry High 15788396
2007 Drosophila Exo84 (ortholog of EXOC8) is required for apical epithelial identity; loss-of-function causes failure of apical localization of the Crumbs transmembrane protein, mislocalization of adherens junction proteins, defects in apical cuticle secretion, and accumulation of apical and adherens junction proteins in an expanded recycling endosome compartment. Drosophila exo84 mutant analysis, immunofluorescence microscopy, genetic epistasis with dlg/lgl reduction Journal of cell science Medium 17698923
2001 Yeast Exo84p physically associates with the U1 snRNP component Snp1p (two-hybrid and co-immunoprecipitation). A temperature-sensitive exo84 mutation causes increased pre-mRNA:mRNA ratios for RPL30 and actin transcripts, and causes a defect in splicing and prespliceosome formation in vitro, indicating a direct role for Exo84p in pre-mRNA splicing. Two-hybrid assay, co-immunoprecipitation, in vivo pre-mRNA accumulation assay, in vitro splicing assay The Journal of biological chemistry Medium 11425851
2013 During mitosis in budding yeast, the cyclin-dependent kinase Cdk1 bound to mitotic cyclin Clb2 directly phosphorylates Exo84p. This phosphorylation disrupts exocyst complex assembly, inhibits exocytosis of select cargoes, and arrests cell surface expansion before the metaphase-anaphase transition. CDK kinase assay, immunoprecipitation, exocytosis assay, phosphorylation-site mutant analysis, fluorescence microscopy The Journal of cell biology High 23836930
2014 In Candida albicans, CaExo84 is phosphorylated by Cdk1 in a hyphal-specific cyclin Hgc1-dependent manner. Unlike in S. cerevisiae where phosphorylation disrupts exocyst assembly, CaExo84 phosphorylation does not alter its localization but reduces its affinity for phosphatidylserine, allowing it to recycle at the plasma membrane and promote continuous hyphal extension throughout mitosis. CDK phosphorylation assay, localization microscopy, phosphatidylserine binding assay, phosphodeficient/phosphomimetic mutant analysis Molecular biology of the cell Medium 24501427
2017 TBK1 phosphorylates the exocyst subunit Exo84 (EXOC8) upon RalA activation by insulin. Phosphorylation of Exo84 by TBK1 reduces its affinity for RalA, enabling Exo84 release from the exocyst complex and facilitating GLUT4 vesicle fusion at the plasma membrane. Phosphorylation-mimicking or nonphosphorylatable Exo84 mutants both block insulin-stimulated GLUT4 translocation, indicating that dynamic cycling of Exo84 phosphorylation state is required. In vitro kinase assay, TBK1 knockdown/knockout in adipocytes, dominant-negative TBK1 overexpression, TBK1 inhibitor treatment, RalA binding assay, phosphomimetic/phosphodeficient mutant analysis, GLUT4 translocation assay, glucose uptake assay Science signaling High 28325821
2019 Cdk1 also phosphorylates Exo84 in late G1 phase (not only mitosis), disrupting exocyst complex assembly, inhibiting exocytic secretion, and arresting cell growth at the G1/S transition in budding yeast. Phosphodeficient and phosphomimetic exo84 mutants confirm this regulatory mechanism. CDK assay, immunoprecipitation, exocytic secretion assay, conditional cdc mutants, phosphodeficient/phosphomimetic mutant analysis, microscopy The Journal of biological chemistry Medium 31171719
2012 In C. elegans, exoc-8 (exo84 ortholog) loss-of-function causes behavioral defects and, in combination with rab-10 RNAi, causes a significant increase in endocytic vacuole size and upregulation of RAB-10 expression in intestinal epithelial cells, functionally linking EXOC8 to RAB-10-dependent endosomal trafficking. C. elegans mutant analysis, targeted RNAi screen for small GTPases, endocytic marker accumulation assay, fluorescence microscopy PloS one Medium 22389680
2012 RalA binding to exocyst effectors Exo84 (EXOC8) and Sec5 is directly required for migration and invasion of prostate cancer cells; blocking RalA-Exocyst binding causes morphological changes and defects in single and coordinated cell migration. RalA-effector interaction blocking, cell migration assay, invasion assay, morphological analysis PloS one Low 22761837
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, as established by direct binding assays and proximity biotinylation. Proximity biotinylation (BioID), direct binding assays, competitive binding assay with RalB/Sec5/Exo84, exocytosis kinetics assay bioRxivpreprint Low

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Exo84p is an exocyst protein essential for secretion. The Journal of biological chemistry 160 10438536
2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 123 15920473
2005 The structures of exocyst subunit Exo70p and the Exo84p C-terminal domains reveal a common motif. Nature structural & molecular biology 119 16249794
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 32 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 24 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

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