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Showing EXOC2 — SEC5 is a alias.

EXOC2

Exocyst complex component 2 · UniProt Q96KP1

Length
924 aa
Mass
104.1 kDa
Annotated
2026-06-09
24 papers in source corpus 20 papers cited in narrative 20 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

EXOC2/Sec5 is a core subunit of the octameric exocyst complex that tethers vesicles to the plasma membrane for polarized membrane trafficking, and it serves as a direct effector that couples Ral GTPase signaling to vesicle delivery (PMID:12839989, PMID:12575951). Its Ral-binding domain adopts an immunoglobulin-like (IPT) beta-sandwich fold that binds RalA in a GTP-dependent manner through a continuous antiparallel beta-sheet interface, a binding mode mutually exclusive with the other exocyst Ral effector Exo84 (PMID:12839989, PMID:12624092, PMID:15920473). Through this activity Sec5 directs biosynthetic delivery of newly synthesized membrane proteins and recycling-endosome cargo — including E-Cadherin, integrins, and secreted ligands — to specific membrane sites, while being dispensable for regulated synaptic vesicle fusion, establishing it as a selective tether for biosynthetic versus regulated exocytosis (PMID:12575951, PMID:16224820, PMID:18697830). Beyond trafficking, Sec5 acts as a signaling node: RalB-dependent assembly of a Sec5–TBK1 complex activates TBK1 kinase to drive cell-survival and innate immune signaling (PMID:18413258), Sec5 binds GEF-H1 to control RhoA-dependent cytoskeletal tension and integrin-mediated attachment (PMID:26359301), and it binds the InsP3 receptor on phagosomes to promote Ca2+ elevation and TBK1/IRF-3–dependent interferon responses during phagocytosis (PMID:29703257). In humans, biallelic truncating EXOC2 variants abolish protein expression, severely impair exocytosis, and disrupt Arl13b localization to the primary cilium, defining EXOC2 as essential for neuronal vesicle trafficking, ciliogenesis, and brain development (PMID:32639540).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Structural and biochemical work answered how Sec5 physically connects to upstream Ral signaling, establishing it as a direct GTP-dependent RalA effector via a novel domain fold.

    Evidence X-ray crystallography at 2.1 Å, NMR, isothermal titration calorimetry, and site-directed mutagenesis of the Sec5 Ral-binding domain

    PMID:12624092 PMID:12839989

    Open questions at the time
    • Did not establish how Ral binding alters exocyst assembly or membrane targeting in cells
    • Affinity and competition with other Ral effectors not yet resolved
  2. 2003 High

    Drosophila genetics resolved which class of exocytosis Sec5 governs, showing it is required for biosynthetic membrane addition but not for regulated synaptic vesicle fusion.

    Evidence Null alleles in Drosophila with membrane trafficking assays and neuromuscular junction electrophysiology

    PMID:12575951

    Open questions at the time
    • Molecular basis for distinguishing biosynthetic from regulated vesicles not defined
    • Mammalian generality not tested in this study
  3. 2005 High

    Crystallography of the competing RalA–Exo84 complex established that Sec5 and Exo84 are mutually exclusive Ral effectors, implying Ral switches between distinct exocyst configurations.

    Evidence X-ray crystallography of RalA–Exo84 plus mutagenesis and biochemical competition assays

    PMID:15920473

    Open questions at the time
    • Functional consequence of the Sec5-bound versus Exo84-bound state in vivo not resolved
    • Regulation of the switch between effectors unknown
  4. 2005 Medium

    Genetic studies defined the cargo and compartment specificity of Sec5-dependent trafficking, linking it to recycling-endosome-to-membrane delivery and endocytic recycling.

    Evidence Drosophila loss-of-function and truncation alleles, immunolocalization, and Co-IP of exocyst subunits with Rab11 and cargo

    PMID:14681190 PMID:15955846 PMID:16224820

    Open questions at the time
    • Direct vs. indirect role in endocytic recycling not separated from secretory role
    • Mammalian cargo specificity not addressed
  5. 2010 Medium

    Conditional alleles tied Sec5 localization to sites of active membrane addition, showing it is required for cleavage-furrow membrane insertion during cellularization.

    Evidence Temperature-sensitive Drosophila allele with immunofluorescence and membrane protein insertion assays

    PMID:20630948

    Open questions at the time
    • Recruitment mechanism to apical/sub-apical sites not defined
    • Identity of the targeting cue unknown
  6. 2008 Medium

    Biochemical and functional studies revealed a signaling role beyond tethering, with RalB driving a Sec5–TBK1 complex that activates kinase signaling for survival and innate immunity.

    Evidence Complex co-purification, kinase assays, and RNAi in transformed cells

    PMID:18413258

    Open questions at the time
    • Whether full exocyst or free Sec5 mediates TBK1 binding unclear
    • Structural basis of Sec5–TBK1 interaction not determined
  7. 2008 Medium

    Ral control of Sec5 localization was linked to integrin delivery and tumor invasion, connecting exocyst targeting to cell motility.

    Evidence RNAi, Ral-uncoupled Sec5 mutants, co-purification, and motility/invasion assays in prostate tumor cells

    PMID:18697830

    Open questions at the time
    • Direct paxillin binding partner within exocyst not defined
    • Mechanism of localization switch to protrusions unresolved
  8. 2012 Low

    RalA effector partitioning between Sec5 and Exo84 was tied to distinct aspects of polarized migration and invasion.

    Evidence RalA effector mutants, RNAi, and migration/invasion assays

    PMID:22761837

    Open questions at the time
    • Limited resolution of Sec5-specific mechanism vs. Exo84
    • Direct molecular readout absent
  9. 2013 Medium

    TIRF and capacitance measurements refined Sec5's exocytic role to recruitment of newcomer and reserve-pool granules rather than predocked vesicles.

    Evidence siRNA, patch-clamp capacitance, and TIRF microscopy in INS-1 beta cells

    PMID:23844030

    Open questions at the time
    • Molecular step distinguishing newcomer from predocked granules unclear
    • Generalizability beyond beta cells untested
  10. 2015 Medium

    A Sec5–GEF-H1 interaction was identified as the link between exocyst and RhoA-driven cytoskeletal tension and adhesion.

    Evidence Co-IP, dominant-negative disruption, and cellular tension/attachment assays in mesenchymal stem cells

    PMID:26359301

    Open questions at the time
    • Direct vs. complex-mediated Sec5–GEF-H1 binding not resolved
    • Single lab/cell type
  11. 2018 Medium

    Sec5 was shown to bind the InsP3R on phagosomes via a defined helix, coupling phagocytosis to Ca2+ signaling and TBK1/IRF-3-driven interferon responses.

    Evidence Co-IP, Ca2+ imaging, recombinant peptide disruption, phagocytosis and IRF-3 phosphorylation assays

    PMID:29703257

    Open questions at the time
    • Whether exocyst tethering and InsP3R binding are coordinated unclear
    • Single-lab interface mapping
  12. 2020 Medium

    Human loss-of-function variants established EXOC2 as essential for exocytosis, ciliogenesis, and brain development, anchoring the gene to a Mendelian phenotype.

    Evidence Patient-derived cells, Western blot, exocytosis assay, and primary cilia immunofluorescence

    PMID:32639540

    Open questions at the time
    • Mechanistic link between exocyst function and Arl13b ciliary delivery not resolved
    • Tissue-specific requirements not dissected
  13. 2022 Medium

    Sec5 was implicated in immune polarization through a STAT6 interaction controlling M2 macrophage differentiation and pregnancy maintenance.

    Evidence Co-IP, knockdown/overexpression, co-localization, and heterozygous mouse model

    PMID:36313547

    Open questions at the time
    • Direct vs. indirect STAT6 regulation unclear
    • Whether exocyst trafficking underlies the effect untested
  14. 2024 Medium

    Loss-of-function EXOC2 perturbation was shown to lower G4C2 repeat RNA and dipeptide repeat proteins, identifying an unexpected role in regulating expanded-repeat RNA levels in C9ORF72 disease.

    Evidence CRISPR-Cas9 deletion in patient iPSCs, iPSC-derived motor neurons, and antisense oligonucleotide treatment

    PMID:38935506

    Open questions at the time
    • Direct vs. indirect control of repeat RNA not established
    • Mechanism connecting exocyst to RNA levels unknown
  15. 2025 Low

    The NF2 tumor suppressor Merlin was identified as a competitive inhibitor of RalB binding to Sec5 and Exo84, adding a regulatory layer over exocyst-effector engagement.

    Evidence Proximity biotinylation, direct and competitive binding assays, and exocytosis kinetics (preprint)

    PMID:bio_10.1101_2025.06.13.659557

    Open questions at the time
    • Preprint without orthogonal validation
    • Physiological context of Merlin competition unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Sec5 mechanistically switches between its tethering role and its diverse signaling roles (TBK1, GEF-H1, InsP3R, STAT6), and how Ral-effector configuration dictates outcome, remains unresolved.
  • No structural model of full assembled exocyst with Sec5 in cells
  • Coordination between membrane tethering and signaling outputs undefined
  • Mechanism linking exocyst to ciliary cargo and repeat RNA unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2 GO:0005929 cilium 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
ARHGEF2EXOC8ITPR1NF2RALARALBSTAT6TBK1
Complex memberships
exocyst

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 The Ral-binding domain of EXOC2/Sec5 adopts an immunoglobulin-like beta-sandwich (IPT domain) fold and binds RalA in a GTP-dependent manner; crystal structure at 2.1 Å resolution revealed a continuous antiparallel beta-sheet interface, and Sec5 Thr11, Arg27, and RalA Glu38 were shown by isothermal titration calorimetry to be required for complex formation. X-ray crystallography (2.1 Å) plus isothermal titration calorimetry and site-directed mutagenesis The EMBO journal High 12839989
2003 The Ral-binding domain of Sec5 folds into an IPT (immunoglobulin superfamily) domain, representing a novel G-protein effector fold; NMR structure and site-directed mutagenesis mapped the Ral-binding surface on Sec5. NMR spectroscopy and site-directed mutagenesis The Journal of biological chemistry High 12624092
2005 Exo84 and Sec5/EXOC2 competitively and mutually exclusively bind active RalA; crystal structure of the RalA–Exo84 complex plus mutagenesis established that the two exocyst subunits share overlapping binding surfaces on RalA, making them competitive effectors. X-ray crystallography plus mutagenesis binding studies and biochemical competition assays The EMBO journal High 15920473
2003 In Drosophila, loss-of-function of sec5 (EXOC2 ortholog) impairs membrane addition and delivery of newly synthesized membrane proteins (neurite outgrowth, neuromuscular junction expansion), but does not impair synaptic vesicle fusion/neurotransmitter release, demonstrating that Sec5 differentiates between biosynthetic membrane trafficking and regulated exocytosis. Genetic null alleles in Drosophila, membrane trafficking assay, electrophysiology at neuromuscular junction Neuron High 12575951
2005 Drosophila Sec5 (EXOC2 ortholog), together with Sec6 and Sec15, is required for trafficking of DE-Cadherin from Rab11-positive recycling endosomes to the plasma membrane in epithelial cells; loss of sec5 causes DE-Cad accumulation in enlarged Rab11 endosomes. Drosophila loss-of-function genetics, immunofluorescence, co-immunoprecipitation of Sec15 with Rab11 and Sec10 with Armadillo Developmental cell High 16224820
2005 In Drosophila oocytes, Sec5/EXOC2 is unexpectedly present in clathrin-coated pits and vesicles at the plasma membrane; a truncation allele (sec5(E13)) causes defective endocytic recycling of the vitellogenin receptor Yolkless (which accumulates in late endosomal compartments), revealing a role for Sec5 in endocytic recycling in addition to secretory trafficking. Drosophila genetics, immunolocalization, truncation allele analysis The Journal of cell biology Medium 15955846
2003 In Drosophila oogenesis, Sec5/EXOC2 is required for directed membrane traffic of the secreted ligand Gurken and the receptor Yolkless; sec5 germline clones show defects in membrane addition, posterior oocyte positioning, dorsal patterning, and egg size, while cytoskeletal orientation remains correct. Drosophila germline clone analysis, immunofluorescence, membrane trafficking assays Development (Cambridge, England) Medium 14681190
2010 Sec5/EXOC2 is required for Drosophila embryo cellularization: a temperature-sensitive sec5 allele (sec5(ts1)) blocks cleavage furrow invagination and prevents membrane insertion of the zygotic protein Neurotactin; Sec5 concentrates at the apical end of lateral membranes (the major site of membrane addition) during cellularization and later at the sub-apical complex in the polarized epithelium. Temperature-sensitive Drosophila allele, immunofluorescence localization, membrane protein insertion assay Development (Cambridge, England) Medium 20630948
2008 RalB activation promotes a direct interaction between Sec5/EXOC2 and TBK1, leading to TBK1 kinase activation; this RalB–Sec5–TBK1 complex is required for RalB-dependent cell survival signaling in transformed cells and for innate immune pathway activation upon virus infection. Protein complex co-purification, protein kinase assays, RNAi knockdown, cell transformation and survival assays Methods in enzymology Medium 18413258
2008 Ral GTPases control the association of Sec5/EXOC2 with paxillin at focal complexes in prostate tumor cells; Ral-uncoupled Sec5 mutants and RNAi knockdown of RalA or RalB disrupted Exocyst–paxillin interaction and shifted Exocyst localization from lateral membranes to protrusive extensions; this Exocyst localization is required for alpha5-integrin delivery to the plasma membrane and for tumor cell motility and matrix invasiveness. RNAi knockdown, Ral-uncoupled Sec5 mutant overexpression, co-purification, immunofluorescence, cell motility/invasion assays Journal of cell science Medium 18697830
2002 DelGEF (a RanGEF homologue) binds the human Sec5/EXOC2 protein; interaction is Mg2+-dependent and stimulated by GTP or dCTP; knockdown of DelGEF increases extracellular secretion of proteoglycans, implicating the DelGEF–Sec5 interaction in the secretion process. Yeast two-hybrid screen, biochemical binding assay, siRNA knockdown with secretion assay FEBS letters Low 12459492
2013 Sec5/EXOC2 regulates exocytosis of newcomer insulin granules in pancreatic beta cells; Sec5 localizes to insulin granules, and siRNA-mediated knockdown in INS-1 cells selectively impairs recruitment and exocytosis of newcomer granules (which minimally dock at the plasma membrane) and mobilization of reserve-pool granules, while having little effect on predocked granules. siRNA knockdown, patch-clamp membrane capacitance measurement, total internal reflection fluorescence (TIRF) microscopy PloS one Medium 23844030
2015 Dexamethasone-induced SGK1 expression promotes interaction between Sec5/EXOC2 and GEF-H1 (a microtubule-regulated RhoA activator); this Sec5–GEF-H1 interaction is required for GEF-H1 targeting to focal adhesion sites and for dexamethasone-induced cellular tension, fibronectin fibril formation, and integrin-mediated attachment in mesenchymal stem cells. Co-immunoprecipitation, dominant-negative disruption of Sec5–GEF-H1 interaction, cellular tension measurements, immunofluorescence Journal of cell science Medium 26359301
2018 During Candida albicans phagocytosis, SEC5/EXOC2 binds the C-terminal α-helix (H1) of the inositol trisphosphate receptor (InsP3R) on phagosomes, promoting InsP3R channel activity and cytosolic Ca2+ elevation; disruption of this interaction with recombinant H1 peptides attenuates Ca2+ elevation and impairs phagocytosis; additionally, the InsP3R–SEC5 complex recruits TBK1, leading to TBK1 activation, IRF-3 phosphorylation, and type I interferon responses. Co-immunoprecipitation, immunofluorescence, Ca2+ imaging, recombinant peptide disruption, phagocytosis assay, IRF-3 phosphorylation assay BMC biology Medium 29703257
2020 Pathogenic truncating variants in EXOC2 cause nonsense-mediated decay of EXOC2 transcript, undetectable EXOC2 protein, severe reduction in exocytosis and vesicle fusion in patient cells, and defective Arl13b localization to the primary cilium, establishing EXOC2 as essential for neuronal vesicle trafficking and ciliogenesis in humans. Patient-derived cell lines, Western blot, exocytosis assay, immunofluorescence of primary cilia, molecular genetics The Journal of experimental medicine Medium 32639540
2022 SEC5/EXOC2 interacts with STAT6 in macrophages; SEC5 knockdown reduces STAT6 phosphorylation and M2 macrophage polarization, while overexpression promotes them; pSTAT6 and SEC5 co-localize, and SEC5 deficiency in mouse decidual macrophages leads to impaired M2 polarization and pregnancy loss. Co-immunoprecipitation, shRNA knockdown, overexpression, immunofluorescence co-localization, mouse heterozygous knockout model Frontiers in cell and developmental biology Medium 36313547
2020 SEC5/EXOC2 knockdown in trophoblast (HTR-8/SVneo) cells reduces plasma membrane distribution of integrin β1, attenuates InsP3R-mediated cytosolic Ca2+ elevation upon serum stimulation, disrupts F-actin stress fibers, and inhibits cell migration and invasion, placing SEC5 upstream of an integrin/Ca2+/cytoskeleton axis. shRNA knockdown, Ca2+ imaging, BAPTA-AM chelation, immunofluorescence, Matrigel invasion assay Reproduction (Cambridge, England) Low 31705793
2012 RalA binding to Sec5/EXOC2 and Exo84 mediates distinct aspects of cell polarization; blocking RalA–Exocyst interactions causes morphological changes and defects in migration and invasion of prostate cancer cells. RalA effector mutants, RNAi, cell migration and invasion assays PloS one Low 22761837
2024 CRISPR-Cas9 deletion of EXOC2 in C9ORF72-ALS/FTD iPSCs (yielding truncated EXOC2 with partial exocyst function) rescues disease phenotypes by decreasing levels of dipeptide repeat (DPR) proteins and G4C2 repeat-containing RNA, indicating that EXOC2 directly or indirectly regulates G4C2 repeat RNA levels; EXOC2 antisense oligonucleotide treatment in differentiated neurons also decreased expanded G4C2 RNA. CRISPR-Cas9 deletion in patient iPSCs, iPSC-derived motor neurons, antisense oligonucleotide treatment, DPR protein and RNA quantification Cell reports Medium 38935506
2025 Active Merlin (NF2 tumor suppressor) competitively inhibits RalB binding to its exocyst effectors Sec5/EXOC2 and Exo84, and Merlin regulates the kinetics of exocytosis in a RalB-dependent manner; direct binding assays showed RalA and RalB are high-affinity PIP2-dependent Merlin-binding proteins. Proximity biotinylation, direct binding assays, competitive binding assays, exocytosis kinetics assay bioRxivpreprint Low bio_10.1101_2025.06.13.659557

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Drosophila exocyst components Sec5, Sec6, and Sec15 regulate DE-Cadherin trafficking from recycling endosomes to the plasma membrane. Developmental cell 231 16224820
2003 Mutations in the exocyst component Sec5 disrupt neuronal membrane traffic, but neurotransmitter release persists. Neuron 175 12575951
2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 123 15920473
2015 Phytophthora infestans RXLR Effector AVR1 Interacts with Exocyst Component Sec5 to Manipulate Plant Immunity. Plant physiology 110 26336092
2003 Structural basis of the interaction between RalA and Sec5, a subunit of the sec6/8 complex. The EMBO journal 98 12839989
2008 Ral-regulated interaction between Sec5 and paxillin targets Exocyst to focal complexes during cell migration. Journal of cell science 81 18697830
2003 The exocyst component Sec5 is required for membrane traffic and polarity in the Drosophila ovary. Development (Cambridge, England) 55 14681190
2005 The exocyst component Sec5 is present on endocytic vesicles in the oocyte of Drosophila melanogaster. The Journal of cell biology 54 15955846
2015 A closer look at evolution: Variants (SNPs) of genes involved in skin pigmentation, including EXOC2, TYR, TYRP1, and DCT, are associated with 25(OH)D serum concentration. Endocrinology 45 25396269
2010 Sec5, a member of the exocyst complex, mediates Drosophila embryo cellularization. Development (Cambridge, England) 32 20630948
2020 Mutations in the exocyst component EXOC2 cause severe defects in human brain development. The Journal of experimental medicine 31 32639540
2003 Structure of the GTPase-binding domain of Sec5 and elucidation of its Ral binding site. The Journal of biological chemistry 30 12624092
2008 Characterization of RalB-Sec5-TBK1 function in human oncogenesis. Methods in enzymology 22 18413258
2013 Exocyst sec5 regulates exocytosis of newcomer insulin granules underlying biphasic insulin secretion. PloS one 21 23844030
2022 SEC5 is involved in M2 polarization of macrophages via the STAT6 pathway, and its dysfunction in decidual macrophages is associated with recurrent spontaneous abortion. Frontiers in cell and developmental biology 20 36313547
2002 DelGEF, a homologue of the Ran guanine nucleotide exchange factor RanGEF, binds to the exocyst component Sec5 and modulates secretion. FEBS letters 18 12459492
2012 Sec5 and Exo84 mediate distinct aspects of RalA-dependent cell polarization. PloS one 15 22761837
2015 Dexamethasone-induced cellular tension requires a SGK1-stimulated Sec5-GEF-H1 interaction. Journal of cell science 13 26359301
2018 InsP3R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca2+ elevation and TBK1 activity. BMC biology 9 29703257
2020 Silencing SEC5 inhibits trophoblast invasion via integrin/Ca2+ signaling. Reproduction (Cambridge, England) 6 31705793
2021 Phytophthora infestans RXLR effector AVR1 disturbs the growth of Physcomitrium patens without affecting Sec5 localization. PloS one 3 33831039
1997 A conditional sterol esterification defect in yeast having either a sec1 or sec5 mutation in the secretory pathway. Yeast (Chichester, England) 2 9153755
2024 The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD. Cell reports 1 38935506
2021 An exocyst component, Sec5, is essential for ascospore formation in Bipolaris maydis. Mycoscience 1 37089464

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