{"gene":"SYTL3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2001,"finding":"SYTL3 (Slp3) was identified as a novel C-terminal-type tandem C2 protein (synaptotagmin-like protein family). Subcellular fractionation showed it is a peripheral membrane protein. The C2A domain of Slp3 showed Ca2+-dependent phospholipid binding activity, making it a Ca2+-dependent isoform unlike Slp1 and Slp2. The C-terminus of Slp3 bound neurexin Iα in vitro.","method":"Subcellular fractionation, phospholipid binding experiments, in vitro binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (fractionation, lipid binding, in vitro pulldown) in a single lab study","pmids":["11243866"],"is_preprint":false},{"year":2001,"finding":"Sequence alignment of Slp3-a with other Slp family members revealed two conserved N-terminal regions (SHD1 and SHD2, Slp homology domains) which may function as protein interaction sites. The SHD1 and SHD2 of Slp3-a are separated by a putative Zn2+-binding sequence. Two alternative splicing isoforms of Slp3 were identified: Slp3-a and Slp3-b, sharing the same C-terminal tandem C2 structures but differing in N-terminal sequences.","method":"Molecular cloning, sequence alignment, RT-PCR tissue distribution analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — sequence/cloning analysis with no direct functional validation of the SHD domains","pmids":["11327731"],"is_preprint":false},{"year":2002,"finding":"The C2A domain of Slp3 exhibits Ca2+-dependent phospholipid-binding activity. Unlike other C-type tandem C2 proteins requiring five conserved acidic residues in Ca2+-binding loops, the Slp3 C2A domain contains only one conserved acidic residue in loop 1. Site-directed mutagenesis identified Glu-336, Glu-337 in Ca2+-binding loop 1 and a polybasic sequence (Lys-359, Lys-360, Lys-361) in the β-4 strand as crucial for Ca2+-dependent phospholipid binding, unlike the analogous region in synaptotagmin I C2A which is dispensable.","method":"In vitro Ca2+-dependent phospholipid binding assay, site-directed mutagenesis, chimeric domain analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution combined with mutagenesis and chimeric analysis establishing the atypical mechanism","pmids":["12049610"],"is_preprint":false},{"year":2002,"finding":"Expression of Slp3-a (which contains the N-terminal Rab27A-binding SHD domain), but not Slp3-b (lacking this domain), promotes neuropeptide Y (NPY) secretion in PC12 cells, indicating that Slp3-a controls regulated dense-core vesicle exocytosis via binding to Rab27A. This is in contrast to Slp4-a/granuphilin-a, which inhibits secretion.","method":"Overexpression in PC12 cells, NPY secretion assay, immunocytochemistry, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue with domain-deletion variant (Slp3-b lacking Rab27A-binding domain as control) in defined secretion assay, single lab","pmids":["12176990"],"is_preprint":false},{"year":2001,"finding":"Melanophilin (Mlph/leaden), a protein with homology to Rab effectors including Slp3-a, was identified as a critical component of the melanosome transport machinery, supporting the model that Slp3-a family members function as Rab effectors in vesicle transport. Mlph possesses two Zn2+-binding CX2CX13,14CX2C motifs and an aromatic-rich region critical for Rab binding, but unlike Slp3-a, lacks two Ca2+-binding C2 domains.","method":"Genetic mapping of leaden locus, sequence homology analysis, functional complementation studies in mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural/sequence comparison relevant to Slp3-a family function, no direct experiments on Slp3 itself","pmids":["11504925"],"is_preprint":false},{"year":2012,"finding":"Slp3 (SYTL3) functions as a Rab27a effector in cytotoxic T lymphocytes (CTLs) and interacts with kinesin-1 through the tetratricopeptide repeat (TPR) domain of kinesin-1 light chain. The Rab27a/Slp3/kinesin-1 transport complex mediates terminal transport and secretion of lytic granules to the immune synapse. Inhibition of this complex impairs lytic granule secretion.","method":"Co-immunoprecipitation, knockdown/inhibition studies, live-cell imaging, CTL killing assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying complex components, functional inhibition with defined phenotype in CTL killing, replicated by multiple approaches in same study","pmids":["22308290"],"is_preprint":false},{"year":2015,"finding":"Increasing expression of Slp3 in Chediak-Higashi syndrome (LYST-deficient) CTLs restored the dynamics and secretory ability of cytotoxic granules at the immunological synapse, placing Slp3 downstream of LYST in the lytic granule exocytosis pathway.","method":"Overexpression rescue in patient-derived CHS CTLs, confocal microscopy, correlative light-electron microscopy","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by rescue experiment in patient cells with defined functional readout, single lab","pmids":["25425525"],"is_preprint":false},{"year":2015,"finding":"Slp3 (SYTL3) is required for Rab27a-dependent association of HIV-1 Pr55(Gag) with the plasma membrane of CD4+ T cells. Screening of Rab27a effectors identified Slp2a, Slp3, and Slac2b as required for Pr55(Gag) membrane association, linking SYTL3 to HIV-1 assembly downstream of Rab27a.","method":"RNAi knockdown, confocal microscopy, Pr55(Gag) membrane association assay in CD4+ T cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown with defined molecular readout (Gag membrane association), single lab","pmids":["25940347"],"is_preprint":false},{"year":2016,"finding":"In mast cells, Slp3 is the critical effector linking kinesin-1 to Rab27b-associated secretory granules. Kinesin-1 recruitment to the Slp3/Rab27b effector complex is independent of microtubule reorganization but requires PI3K activity upon IgE receptor stimulation. The PI3K-dependent formation of the kinesin-1/Slp3/Rab27b complex is critical for microtubule-dependent secretory granule movement required for mast cell degranulation and IgE-mediated anaphylaxis in vivo.","method":"Kif5b conditional knockout mice, bone marrow-derived mast cell degranulation assays, passive systemic anaphylaxis model, co-immunoprecipitation, pharmacological PI3K inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with anaphylaxis phenotype, ex vivo degranulation assays, Co-IP demonstrating complex, and PI3K inhibitor dissecting the signaling requirement — multiple orthogonal methods","pmids":["27810912"],"is_preprint":false},{"year":2008,"finding":"Slp3 (Slp1/Slp2-a) proteins localize predominantly to the plasma membrane of both human and mouse CTLs. In CTLs, Slp3-a expression was not detected (only Slp1 and Slp2-a were found), indicating cell-type-specific expression of Slp family members.","method":"RT-PCR screening, immunofluorescence/confocal microscopy, flow cytometry in human and mouse CTLs","journal":"Traffic (Copenhagen, Denmark)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — negative expression result for Slp3-a in CTLs with localization data for Slp1/Slp2-a; limited mechanistic data directly about SYTL3","pmids":["18266782"],"is_preprint":false},{"year":2020,"finding":"Knockdown of SYTL3 (or Rab27b) in bladder cancer cells increased intracellular BCG quantity and cytotoxicity, while overexpression of Rab27b reduced them. This indicates that SYTL3 functions as an effector of Rab27b to mediate exocytosis of BCG from urothelial cells, contributing to BCG therapy resistance.","method":"shRNA knockdown, overexpression, mouse orthotopic xenograft model, intracellular BCG quantification","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readout (bacterial exocytosis), in vivo validation, single lab","pmids":["32737155"],"is_preprint":false},{"year":2021,"finding":"SYTL3 knockout in human neurons (hESC-derived) or knockdown of Sytl3 in embryonic mouse cortex markedly promotes neuronal migration. SYTL3-KO caused abnormal distribution of deep-layer neurons in brain organoids and reduced presynaptic neurotransmitter release. SYTL3-KO-accelerated neuronal migration is modulated by high expression of matrix metalloproteinases.","method":"CRISPR knockout in hESC-derived neurons, in utero shRNA knockdown in mouse cortex, brain organoids, MMP inhibitor experiments, neurotransmitter release assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two model systems (human neurons and mouse cortex) with defined cellular phenotypes and downstream MMP mechanism, single lab","pmids":["33657377"],"is_preprint":false},{"year":2022,"finding":"In mast cells, Slp3 (a cargo adaptor) recruitment to secretory granules was independent of kinesin-1 motor association: kinesore treatment (which activates kinesin-1) had no effect on Slp3 levels in a granule-enriched biochemical fraction, even though it inhibited granule transport and exocytosis. This dissociates granule-adaptor loading from motor recruitment.","method":"shRNA Kif5b knockdown, live-cell imaging, biochemical granule fractionation, kinesore pharmacological treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical fractionation and imaging with pharmacological tool, but single lab and single method for the Slp3-specific finding","pmids":["35316306"],"is_preprint":false}],"current_model":"SYTL3/Slp3 is a peripheral membrane Rab27a/b effector protein with an N-terminal Slp homology domain (SHD) that binds active Rab27a/b and C-terminal tandem C2 domains (the C2A domain being an atypical Ca2+-dependent phospholipid-binding module requiring Glu-336/337 and a polybasic sequence); it forms a tripartite complex with Rab27a/b and kinesin-1 (via the kinesin light chain TPR domain) that drives terminal microtubule-dependent transport and exocytosis of secretory/lytic granules in cytotoxic T lymphocytes and mast cells (the latter requiring PI3K signaling for complex assembly), and additionally regulates cortical neuronal migration through matrix metalloproteinases and mediates Rab27b-dependent bacterial exocytosis in bladder epithelial cells."},"narrative":{"mechanistic_narrative":"SYTL3 (Slp3) is a peripheral membrane Rab27 effector of the synaptotagmin-like protein family that couples Rab27-decorated secretory granules to microtubule motors to drive their terminal transport and exocytosis [PMID:11243866, PMID:22308290]. It is a C-terminal-type tandem C2 protein whose C2A domain is an atypical Ca2+-dependent phospholipid-binding module that, unlike canonical synaptotagmin C2A, depends on Glu-336/Glu-337 in Ca2+-binding loop 1 together with a polybasic Lys-359/360/361 sequence in the β-4 strand [PMID:11243866, PMID:12049610]. Its N-terminal Slp homology domain confers Rab27 binding: the Rab27A-binding isoform Slp3-a, but not the SHD-lacking Slp3-b, promotes regulated dense-core vesicle exocytosis [PMID:12176990]. In cytotoxic T lymphocytes, SYTL3 acts as a Rab27a effector that bridges to kinesin-1 through the TPR domain of the kinesin light chain, forming a Rab27a/Slp3/kinesin-1 complex that delivers lytic granules to the immune synapse, and it operates downstream of LYST in this exocytic pathway [PMID:22308290, PMID:25425525]. In mast cells the analogous Rab27b/Slp3/kinesin-1 complex assembles in a PI3K-dependent manner upon IgE receptor stimulation to drive secretory-granule transport, degranulation, and anaphylaxis in vivo, with granule loading of Slp3 being separable from kinesin-1 motor recruitment [PMID:27810912, PMID:35316306]. Beyond classical secretion, SYTL3 mediates Rab27b-dependent exocytosis of intracellular BCG from bladder urothelial cells and restrains cortical neuronal migration via control of matrix metalloproteinases [PMID:32737155, PMID:33657377].","teleology":[{"year":2001,"claim":"Establishing SYTL3 as a distinct synaptotagmin-like protein answered whether a new tandem-C2 family member existed with potential membrane and protein-interaction roles, defining its domain architecture.","evidence":"Molecular cloning, sequence alignment, subcellular fractionation and in vitro binding in a single study","pmids":["11243866","11327731"],"confidence":"Medium","gaps":["Functional role of the SHD1/SHD2 domains not directly tested","Physiological relevance of in vitro neurexin Iα binding unestablished","No cellular phenotype assigned"]},{"year":2002,"claim":"Mutagenesis of the C2A domain resolved how SYTL3 achieves Ca2+-dependent lipid binding despite lacking the canonical acidic residue set, defining an atypical Ca2+-sensing mechanism.","evidence":"In vitro Ca2+-dependent phospholipid binding, site-directed mutagenesis and chimeric domain analysis","pmids":["12049610"],"confidence":"High","gaps":["Structural basis not resolved","Lipid specificity in a cellular membrane context not defined","Link between Ca2+ sensing and a secretion step not established"]},{"year":2002,"claim":"Comparing Rab27A-binding (Slp3-a) versus non-binding (Slp3-b) isoforms showed that SHD-mediated Rab27A binding is required for SYTL3 to promote regulated exocytosis, distinguishing it from inhibitory Slp family members.","evidence":"Overexpression of isoforms in PC12 cells with NPY secretion assay and fractionation","pmids":["12176990"],"confidence":"Medium","gaps":["Overexpression system may not reflect endogenous regulation","Downstream transport machinery not yet identified","Single cell type tested"]},{"year":2012,"claim":"Identifying the Rab27a/Slp3/kinesin-1 complex answered how lytic granules reach the immune synapse, placing SYTL3 as the molecular bridge between the Rab GTPase and the microtubule motor.","evidence":"Reciprocal co-immunoprecipitation, knockdown/inhibition, live imaging and CTL killing assays","pmids":["22308290"],"confidence":"High","gaps":["Stoichiometry and assembly order of the tripartite complex unresolved","Regulation of complex formation in CTLs not defined","Role of the C2 Ca2+-sensing domain in this complex untested"]},{"year":2015,"claim":"Rescue of CHS CTLs by SYTL3 expression positioned it downstream of LYST, ordering the lytic-granule exocytosis pathway.","evidence":"Overexpression rescue in patient-derived CHS CTLs with confocal and correlative light-electron microscopy","pmids":["25425525"],"confidence":"Medium","gaps":["Mechanistic link between LYST and SYTL3 not defined","Rescue relies on overexpression rather than endogenous restoration"]},{"year":2015,"claim":"A Rab27a-effector screen revealed SYTL3 is required for HIV-1 Gag membrane association, extending its role to viral assembly downstream of Rab27a.","evidence":"RNAi knockdown and Gag membrane association assay in CD4+ T cells","pmids":["25940347"],"confidence":"Medium","gaps":["Direct role of SYTL3 in Gag trafficking versus indirect effect not separated","No reconstitution of the implicated transport step"]},{"year":2016,"claim":"Mast cell studies showed the Rab27b/Slp3/kinesin-1 complex assembles in a PI3K-dependent manner upon IgE signaling, defining a signaling input that licenses motor recruitment and degranulation in vivo.","evidence":"Kif5b conditional knockout mice, BMMC degranulation, anaphylaxis model, Co-IP and PI3K inhibition","pmids":["27810912"],"confidence":"High","gaps":["Molecular target of PI3K signaling in complex assembly not identified","Direct contribution of endogenous SYTL3 loss-of-function not isolated"]},{"year":2020,"claim":"Knockdown and overexpression in bladder cancer cells established SYTL3 as a Rab27b effector mediating exocytosis of intracellular BCG, linking it to BCG therapy resistance.","evidence":"shRNA knockdown, overexpression, orthotopic xenograft and intracellular BCG quantification","pmids":["32737155"],"confidence":"Medium","gaps":["Mechanism of bacterial cargo recognition unknown","Single lab and cancer cell context"]},{"year":2021,"claim":"Loss-of-function in human neurons and mouse cortex revealed SYTL3 restrains neuronal migration via matrix metalloproteinases and supports presynaptic release, extending its role beyond classical granule exocytosis.","evidence":"CRISPR knockout in hESC-derived neurons, in utero shRNA knockdown, brain organoids, MMP inhibitor and neurotransmitter release assays","pmids":["33657377"],"confidence":"Medium","gaps":["Connection between Rab27/kinesin-1 trafficking role and MMP regulation unclear","Whether the C2/SHD domains mediate the migration phenotype untested"]},{"year":2022,"claim":"Pharmacological dissection in mast cells showed SYTL3 granule loading is independent of kinesin-1 motor recruitment, separating adaptor loading from motor engagement in the transport pathway.","evidence":"shRNA Kif5b knockdown, live imaging, granule fractionation and kinesore treatment","pmids":["35316306"],"confidence":"Medium","gaps":["Single biochemical method for the Slp3-specific result","Signal that triggers motor recruitment to pre-loaded adaptor not identified"]},{"year":null,"claim":"How the atypical C2A Ca2+/lipid-sensing module is integrated with Rab27/kinesin-1-driven transport to time and target granule fusion across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the SYTL3/Rab27/kinesin-1 complex","Ca2+ sensing not linked to a defined fusion or docking step in vivo","Mechanism connecting trafficking role to MMP-dependent neuronal migration unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8]}],"complexes":["Rab27a/Slp3/kinesin-1 transport complex","Rab27b/Slp3/kinesin-1 transport complex"],"partners":["RAB27A","RAB27B","KLC1","KIF5B","NRXN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4VX76","full_name":"Synaptotagmin-like protein 3","aliases":["Exophilin-6"],"length_aa":610,"mass_kda":68.6,"function":"May act as Rab effector protein and play a role in vesicle trafficking. Binds phospholipids in the presence of calcium ions (By similarity)","subcellular_location":"Endomembrane system","url":"https://www.uniprot.org/uniprotkb/Q4VX76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYTL3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SYTL3","total_profiled":1310},"omim":[{"mim_id":"620973","title":"SYNAPTOTAGMIN-LIKE 3; SYTL3","url":"https://www.omim.org/entry/620973"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":47.0}],"url":"https://www.proteinatlas.org/search/SYTL3"},"hgnc":{"alias_symbol":["SLP3","exophilin-6"],"prev_symbol":[]},"alphafold":{"accession":"Q4VX76","domains":[{"cath_id":"3.30.40.10","chopping":"13-53_60-147","consensus_level":"high","plddt":83.551,"start":13,"end":147},{"cath_id":"2.60.40.150","chopping":"310-433","consensus_level":"high","plddt":91.6596,"start":310,"end":433},{"cath_id":"2.60.40.150","chopping":"450-461_480-610","consensus_level":"high","plddt":83.9631,"start":450,"end":610}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4VX76","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4VX76-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4VX76-F1-predicted_aligned_error_v6.png","plddt_mean":71.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYTL3","jax_strain_url":"https://www.jax.org/strain/search?query=SYTL3"},"sequence":{"accession":"Q4VX76","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4VX76.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4VX76/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4VX76"}},"corpus_meta":[{"pmid":"6631413","id":"PMC_6631413","title":"Plasmids, recombination and chromosome mapping in Streptomyces lividans 66.","date":"1983","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/6631413","citation_count":381,"is_preprint":false},{"pmid":"11504925","id":"PMC_11504925","title":"Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11504925","citation_count":210,"is_preprint":false},{"pmid":"17167420","id":"PMC_17167420","title":"A stomatin-domain protein essential for touch sensation in the mouse.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17167420","citation_count":205,"is_preprint":false},{"pmid":"22308290","id":"PMC_22308290","title":"Terminal transport of lytic granules to the immune synapse is mediated by the kinesin-1/Slp3/Rab27a complex.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22308290","citation_count":94,"is_preprint":false},{"pmid":"11243866","id":"PMC_11243866","title":"Synaptotagmin-like protein 1-3: a novel family of C-terminal-type tandem C2 proteins.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11243866","citation_count":90,"is_preprint":false},{"pmid":"23709624","id":"PMC_23709624","title":"The genome sequence of Streptomyces lividans 66 reveals a novel tRNA-dependent peptide biosynthetic system within a metal-related genomic island.","date":"2013","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/23709624","citation_count":86,"is_preprint":false},{"pmid":"21646512","id":"PMC_21646512","title":"Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21646512","citation_count":85,"is_preprint":false},{"pmid":"18266782","id":"PMC_18266782","title":"Slp1 and Slp2-a localize to the plasma membrane of CTL and contribute to secretion from the immunological synapse.","date":"2008","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/18266782","citation_count":78,"is_preprint":false},{"pmid":"11327731","id":"PMC_11327731","title":"Novel splicing isoforms of synaptotagmin-like proteins 2 and 3: identification of the Slp homology domain.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11327731","citation_count":75,"is_preprint":false},{"pmid":"12176990","id":"PMC_12176990","title":"Slp4-a/granuphilin-a regulates dense-core vesicle exocytosis in PC12 cells.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12176990","citation_count":71,"is_preprint":false},{"pmid":"25940347","id":"PMC_25940347","title":"Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25940347","citation_count":68,"is_preprint":false},{"pmid":"1494353","id":"PMC_1494353","title":"Cloning and DNA sequence analysis of the mercury resistance genes of Streptomyces lividans.","date":"1992","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/1494353","citation_count":61,"is_preprint":false},{"pmid":"25425525","id":"PMC_25425525","title":"LYST controls the biogenesis of the endosomal compartment required for secretory lysosome function.","date":"2015","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/25425525","citation_count":59,"is_preprint":false},{"pmid":"23082221","id":"PMC_23082221","title":"Genome-wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23082221","citation_count":45,"is_preprint":false},{"pmid":"12239636","id":"PMC_12239636","title":"Cloning and characterization of SLP3: a novel member of the stomatin family expressed by olfactory receptor neurons.","date":"2002","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/12239636","citation_count":39,"is_preprint":false},{"pmid":"27810912","id":"PMC_27810912","title":"Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27810912","citation_count":37,"is_preprint":false},{"pmid":"18267007","id":"PMC_18267007","title":"Slipins: ancient origin, duplication and diversification of the stomatin protein family.","date":"2008","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/18267007","citation_count":36,"is_preprint":false},{"pmid":"31788113","id":"PMC_31788113","title":"Identification of hub genes and key pathways associated with the progression of gynecological cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31788113","citation_count":35,"is_preprint":false},{"pmid":"27854551","id":"PMC_27854551","title":"Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas.","date":"2017","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27854551","citation_count":32,"is_preprint":false},{"pmid":"12049610","id":"PMC_12049610","title":"The C2A domain of synaptotagmin-like protein 3 (Slp3) is an atypical calcium-dependent phospholipid-binding machine: comparison with the C2A domain of synaptotagmin I.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12049610","citation_count":31,"is_preprint":false},{"pmid":"32737155","id":"PMC_32737155","title":"Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis.","date":"2020","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32737155","citation_count":28,"is_preprint":false},{"pmid":"22361517","id":"PMC_22361517","title":"Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.","date":"2012","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/22361517","citation_count":22,"is_preprint":false},{"pmid":"19032151","id":"PMC_19032151","title":"A single conserved proline residue determines the membrane topology of stomatin.","date":"2009","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/19032151","citation_count":22,"is_preprint":false},{"pmid":"36604669","id":"PMC_36604669","title":"Coordinated reprogramming of renal cancer transcriptome, metabolome and secretome associates with immune tumor infiltration.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/36604669","citation_count":16,"is_preprint":false},{"pmid":"32153525","id":"PMC_32153525","title":"SPT20 Regulates the Hog1-MAPK Pathway and Is Involved in Candida albicans Response to Hyperosmotic Stress.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32153525","citation_count":15,"is_preprint":false},{"pmid":"29389961","id":"PMC_29389961","title":"The Candida albicans stress response gene Stomatin-Like Protein 3 is implicated in ROS-induced apoptotic-like death of yeast phase cells.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29389961","citation_count":14,"is_preprint":false},{"pmid":"35316306","id":"PMC_35316306","title":"Mast cell granule motility and exocytosis is driven by dynamic microtubule formation and kinesin-1 motor function.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35316306","citation_count":13,"is_preprint":false},{"pmid":"27285458","id":"PMC_27285458","title":"Characterization of Three Different Unusual S-Layer Proteins from Viridibacillus arvi JG-B58 That Exhibits Two Super-Imposed S-Layer Proteins.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27285458","citation_count":10,"is_preprint":false},{"pmid":"34458338","id":"PMC_34458338","title":"Effect of SYTL3-SLC22A3 Variants, Their Haplotypes, and G × E Interactions on Serum Lipid Levels and the Risk of Coronary Artery Disease and Ischaemic Stroke.","date":"2021","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34458338","citation_count":9,"is_preprint":false},{"pmid":"33657377","id":"PMC_33657377","title":"Transcriptional networks identify synaptotagmin-like 3 as a regulator of cortical neuronal migration during early neurodevelopment.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33657377","citation_count":8,"is_preprint":false},{"pmid":"36872978","id":"PMC_36872978","title":"Cell Protection and Crystal Endocytosis Inhibition by Sulfated Laminaria Polysaccharides Against Nano-COM-Induced Oxidative Damage in Renal Epithelial Cells.","date":"2023","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/36872978","citation_count":8,"is_preprint":false},{"pmid":"32108034","id":"PMC_32108034","title":"The Search for Molecular Markers in a Gene-Orphan Case Study of a Pediatric Spinal Cord Pilocytic Astrocytoma.","date":"2020","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32108034","citation_count":8,"is_preprint":false},{"pmid":"36918797","id":"PMC_36918797","title":"Identification of candidate genomic regions for egg yolk moisture content based on a genome-wide association study.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36918797","citation_count":8,"is_preprint":false},{"pmid":"34367243","id":"PMC_34367243","title":"SYTL3-SLC22A3 Single-Nucleotide Polymorphisms and Gene-Gene/Environment Interactions on the Risk of Hyperlipidemia.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34367243","citation_count":7,"is_preprint":false},{"pmid":"38001974","id":"PMC_38001974","title":"Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/38001974","citation_count":5,"is_preprint":false},{"pmid":"39641539","id":"PMC_39641539","title":"Mitochondrial targeting of Candida albicans SPFH proteins and requirement of stomatins for SDS-induced stress tolerance.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/39641539","citation_count":3,"is_preprint":false},{"pmid":"40963613","id":"PMC_40963613","title":"Assessment of gene signatures following the inhibition of IL-23: a study to evaluate the mechanistic effects behind the clinical efficacy of guselkumab in patients with psoriatic arthritis.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40963613","citation_count":1,"is_preprint":false},{"pmid":"37612620","id":"PMC_37612620","title":"Genome-wide analysis of circRNA regulation during spleen development of Chinese indigenous breed Meishan pigs.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37612620","citation_count":1,"is_preprint":false},{"pmid":"38204734","id":"PMC_38204734","title":"Different Degrees of Sulfated Laminaria Polysaccharides Recovered Damaged HK-2 Cells and Inhibited Adhesion of Nano-COM and Nano-COD Crystals.","date":"2024","source":"Bioinorganic chemistry and applications","url":"https://pubmed.ncbi.nlm.nih.gov/38204734","citation_count":1,"is_preprint":false},{"pmid":"41857782","id":"PMC_41857782","title":"Cuproptosis of endothelial cells in a hypoxic environment: from molecular classification to PMAIP1-targeted intervention.","date":"2026","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/41857782","citation_count":0,"is_preprint":false},{"pmid":"42032457","id":"PMC_42032457","title":"Single-cell transcriptomic and chromatin accessibility atlas of peripheral blood mononuclear cells reveals immune cell heterogeneity and breed-specific characteristics in Duroc and Meishan pigs.","date":"2026","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42032457","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24948,"output_tokens":3617,"usd":0.064549,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11145,"output_tokens":3679,"usd":0.07385,"stage2_stop_reason":"end_turn"},"total_usd":0.138399,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SYTL3 (Slp3) was identified as a novel C-terminal-type tandem C2 protein (synaptotagmin-like protein family). Subcellular fractionation showed it is a peripheral membrane protein. The C2A domain of Slp3 showed Ca2+-dependent phospholipid binding activity, making it a Ca2+-dependent isoform unlike Slp1 and Slp2. The C-terminus of Slp3 bound neurexin Iα in vitro.\",\n      \"method\": \"Subcellular fractionation, phospholipid binding experiments, in vitro binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (fractionation, lipid binding, in vitro pulldown) in a single lab study\",\n      \"pmids\": [\"11243866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sequence alignment of Slp3-a with other Slp family members revealed two conserved N-terminal regions (SHD1 and SHD2, Slp homology domains) which may function as protein interaction sites. The SHD1 and SHD2 of Slp3-a are separated by a putative Zn2+-binding sequence. Two alternative splicing isoforms of Slp3 were identified: Slp3-a and Slp3-b, sharing the same C-terminal tandem C2 structures but differing in N-terminal sequences.\",\n      \"method\": \"Molecular cloning, sequence alignment, RT-PCR tissue distribution analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — sequence/cloning analysis with no direct functional validation of the SHD domains\",\n      \"pmids\": [\"11327731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C2A domain of Slp3 exhibits Ca2+-dependent phospholipid-binding activity. Unlike other C-type tandem C2 proteins requiring five conserved acidic residues in Ca2+-binding loops, the Slp3 C2A domain contains only one conserved acidic residue in loop 1. Site-directed mutagenesis identified Glu-336, Glu-337 in Ca2+-binding loop 1 and a polybasic sequence (Lys-359, Lys-360, Lys-361) in the β-4 strand as crucial for Ca2+-dependent phospholipid binding, unlike the analogous region in synaptotagmin I C2A which is dispensable.\",\n      \"method\": \"In vitro Ca2+-dependent phospholipid binding assay, site-directed mutagenesis, chimeric domain analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution combined with mutagenesis and chimeric analysis establishing the atypical mechanism\",\n      \"pmids\": [\"12049610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Expression of Slp3-a (which contains the N-terminal Rab27A-binding SHD domain), but not Slp3-b (lacking this domain), promotes neuropeptide Y (NPY) secretion in PC12 cells, indicating that Slp3-a controls regulated dense-core vesicle exocytosis via binding to Rab27A. This is in contrast to Slp4-a/granuphilin-a, which inhibits secretion.\",\n      \"method\": \"Overexpression in PC12 cells, NPY secretion assay, immunocytochemistry, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with domain-deletion variant (Slp3-b lacking Rab27A-binding domain as control) in defined secretion assay, single lab\",\n      \"pmids\": [\"12176990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Melanophilin (Mlph/leaden), a protein with homology to Rab effectors including Slp3-a, was identified as a critical component of the melanosome transport machinery, supporting the model that Slp3-a family members function as Rab effectors in vesicle transport. Mlph possesses two Zn2+-binding CX2CX13,14CX2C motifs and an aromatic-rich region critical for Rab binding, but unlike Slp3-a, lacks two Ca2+-binding C2 domains.\",\n      \"method\": \"Genetic mapping of leaden locus, sequence homology analysis, functional complementation studies in mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural/sequence comparison relevant to Slp3-a family function, no direct experiments on Slp3 itself\",\n      \"pmids\": [\"11504925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Slp3 (SYTL3) functions as a Rab27a effector in cytotoxic T lymphocytes (CTLs) and interacts with kinesin-1 through the tetratricopeptide repeat (TPR) domain of kinesin-1 light chain. The Rab27a/Slp3/kinesin-1 transport complex mediates terminal transport and secretion of lytic granules to the immune synapse. Inhibition of this complex impairs lytic granule secretion.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/inhibition studies, live-cell imaging, CTL killing assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying complex components, functional inhibition with defined phenotype in CTL killing, replicated by multiple approaches in same study\",\n      \"pmids\": [\"22308290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Increasing expression of Slp3 in Chediak-Higashi syndrome (LYST-deficient) CTLs restored the dynamics and secretory ability of cytotoxic granules at the immunological synapse, placing Slp3 downstream of LYST in the lytic granule exocytosis pathway.\",\n      \"method\": \"Overexpression rescue in patient-derived CHS CTLs, confocal microscopy, correlative light-electron microscopy\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by rescue experiment in patient cells with defined functional readout, single lab\",\n      \"pmids\": [\"25425525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Slp3 (SYTL3) is required for Rab27a-dependent association of HIV-1 Pr55(Gag) with the plasma membrane of CD4+ T cells. Screening of Rab27a effectors identified Slp2a, Slp3, and Slac2b as required for Pr55(Gag) membrane association, linking SYTL3 to HIV-1 assembly downstream of Rab27a.\",\n      \"method\": \"RNAi knockdown, confocal microscopy, Pr55(Gag) membrane association assay in CD4+ T cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown with defined molecular readout (Gag membrane association), single lab\",\n      \"pmids\": [\"25940347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In mast cells, Slp3 is the critical effector linking kinesin-1 to Rab27b-associated secretory granules. Kinesin-1 recruitment to the Slp3/Rab27b effector complex is independent of microtubule reorganization but requires PI3K activity upon IgE receptor stimulation. The PI3K-dependent formation of the kinesin-1/Slp3/Rab27b complex is critical for microtubule-dependent secretory granule movement required for mast cell degranulation and IgE-mediated anaphylaxis in vivo.\",\n      \"method\": \"Kif5b conditional knockout mice, bone marrow-derived mast cell degranulation assays, passive systemic anaphylaxis model, co-immunoprecipitation, pharmacological PI3K inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with anaphylaxis phenotype, ex vivo degranulation assays, Co-IP demonstrating complex, and PI3K inhibitor dissecting the signaling requirement — multiple orthogonal methods\",\n      \"pmids\": [\"27810912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Slp3 (Slp1/Slp2-a) proteins localize predominantly to the plasma membrane of both human and mouse CTLs. In CTLs, Slp3-a expression was not detected (only Slp1 and Slp2-a were found), indicating cell-type-specific expression of Slp family members.\",\n      \"method\": \"RT-PCR screening, immunofluorescence/confocal microscopy, flow cytometry in human and mouse CTLs\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — negative expression result for Slp3-a in CTLs with localization data for Slp1/Slp2-a; limited mechanistic data directly about SYTL3\",\n      \"pmids\": [\"18266782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of SYTL3 (or Rab27b) in bladder cancer cells increased intracellular BCG quantity and cytotoxicity, while overexpression of Rab27b reduced them. This indicates that SYTL3 functions as an effector of Rab27b to mediate exocytosis of BCG from urothelial cells, contributing to BCG therapy resistance.\",\n      \"method\": \"shRNA knockdown, overexpression, mouse orthotopic xenograft model, intracellular BCG quantification\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular readout (bacterial exocytosis), in vivo validation, single lab\",\n      \"pmids\": [\"32737155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SYTL3 knockout in human neurons (hESC-derived) or knockdown of Sytl3 in embryonic mouse cortex markedly promotes neuronal migration. SYTL3-KO caused abnormal distribution of deep-layer neurons in brain organoids and reduced presynaptic neurotransmitter release. SYTL3-KO-accelerated neuronal migration is modulated by high expression of matrix metalloproteinases.\",\n      \"method\": \"CRISPR knockout in hESC-derived neurons, in utero shRNA knockdown in mouse cortex, brain organoids, MMP inhibitor experiments, neurotransmitter release assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two model systems (human neurons and mouse cortex) with defined cellular phenotypes and downstream MMP mechanism, single lab\",\n      \"pmids\": [\"33657377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mast cells, Slp3 (a cargo adaptor) recruitment to secretory granules was independent of kinesin-1 motor association: kinesore treatment (which activates kinesin-1) had no effect on Slp3 levels in a granule-enriched biochemical fraction, even though it inhibited granule transport and exocytosis. This dissociates granule-adaptor loading from motor recruitment.\",\n      \"method\": \"shRNA Kif5b knockdown, live-cell imaging, biochemical granule fractionation, kinesore pharmacological treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical fractionation and imaging with pharmacological tool, but single lab and single method for the Slp3-specific finding\",\n      \"pmids\": [\"35316306\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYTL3/Slp3 is a peripheral membrane Rab27a/b effector protein with an N-terminal Slp homology domain (SHD) that binds active Rab27a/b and C-terminal tandem C2 domains (the C2A domain being an atypical Ca2+-dependent phospholipid-binding module requiring Glu-336/337 and a polybasic sequence); it forms a tripartite complex with Rab27a/b and kinesin-1 (via the kinesin light chain TPR domain) that drives terminal microtubule-dependent transport and exocytosis of secretory/lytic granules in cytotoxic T lymphocytes and mast cells (the latter requiring PI3K signaling for complex assembly), and additionally regulates cortical neuronal migration through matrix metalloproteinases and mediates Rab27b-dependent bacterial exocytosis in bladder epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SYTL3 (Slp3) is a peripheral membrane Rab27 effector of the synaptotagmin-like protein family that couples Rab27-decorated secretory granules to microtubule motors to drive their terminal transport and exocytosis [#0, #5]. It is a C-terminal-type tandem C2 protein whose C2A domain is an atypical Ca2+-dependent phospholipid-binding module that, unlike canonical synaptotagmin C2A, depends on Glu-336/Glu-337 in Ca2+-binding loop 1 together with a polybasic Lys-359/360/361 sequence in the β-4 strand [#0, #2]. Its N-terminal Slp homology domain confers Rab27 binding: the Rab27A-binding isoform Slp3-a, but not the SHD-lacking Slp3-b, promotes regulated dense-core vesicle exocytosis [#3]. In cytotoxic T lymphocytes, SYTL3 acts as a Rab27a effector that bridges to kinesin-1 through the TPR domain of the kinesin light chain, forming a Rab27a/Slp3/kinesin-1 complex that delivers lytic granules to the immune synapse, and it operates downstream of LYST in this exocytic pathway [#5, #6]. In mast cells the analogous Rab27b/Slp3/kinesin-1 complex assembles in a PI3K-dependent manner upon IgE receptor stimulation to drive secretory-granule transport, degranulation, and anaphylaxis in vivo, with granule loading of Slp3 being separable from kinesin-1 motor recruitment [#8, #12]. Beyond classical secretion, SYTL3 mediates Rab27b-dependent exocytosis of intracellular BCG from bladder urothelial cells and restrains cortical neuronal migration via control of matrix metalloproteinases [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing SYTL3 as a distinct synaptotagmin-like protein answered whether a new tandem-C2 family member existed with potential membrane and protein-interaction roles, defining its domain architecture.\",\n      \"evidence\": \"Molecular cloning, sequence alignment, subcellular fractionation and in vitro binding in a single study\",\n      \"pmids\": [\"11243866\", \"11327731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of the SHD1/SHD2 domains not directly tested\",\n        \"Physiological relevance of in vitro neurexin Iα binding unestablished\",\n        \"No cellular phenotype assigned\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mutagenesis of the C2A domain resolved how SYTL3 achieves Ca2+-dependent lipid binding despite lacking the canonical acidic residue set, defining an atypical Ca2+-sensing mechanism.\",\n      \"evidence\": \"In vitro Ca2+-dependent phospholipid binding, site-directed mutagenesis and chimeric domain analysis\",\n      \"pmids\": [\"12049610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis not resolved\",\n        \"Lipid specificity in a cellular membrane context not defined\",\n        \"Link between Ca2+ sensing and a secretion step not established\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Comparing Rab27A-binding (Slp3-a) versus non-binding (Slp3-b) isoforms showed that SHD-mediated Rab27A binding is required for SYTL3 to promote regulated exocytosis, distinguishing it from inhibitory Slp family members.\",\n      \"evidence\": \"Overexpression of isoforms in PC12 cells with NPY secretion assay and fractionation\",\n      \"pmids\": [\"12176990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Overexpression system may not reflect endogenous regulation\",\n        \"Downstream transport machinery not yet identified\",\n        \"Single cell type tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying the Rab27a/Slp3/kinesin-1 complex answered how lytic granules reach the immune synapse, placing SYTL3 as the molecular bridge between the Rab GTPase and the microtubule motor.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, knockdown/inhibition, live imaging and CTL killing assays\",\n      \"pmids\": [\"22308290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and assembly order of the tripartite complex unresolved\",\n        \"Regulation of complex formation in CTLs not defined\",\n        \"Role of the C2 Ca2+-sensing domain in this complex untested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Rescue of CHS CTLs by SYTL3 expression positioned it downstream of LYST, ordering the lytic-granule exocytosis pathway.\",\n      \"evidence\": \"Overexpression rescue in patient-derived CHS CTLs with confocal and correlative light-electron microscopy\",\n      \"pmids\": [\"25425525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between LYST and SYTL3 not defined\",\n        \"Rescue relies on overexpression rather than endogenous restoration\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A Rab27a-effector screen revealed SYTL3 is required for HIV-1 Gag membrane association, extending its role to viral assembly downstream of Rab27a.\",\n      \"evidence\": \"RNAi knockdown and Gag membrane association assay in CD4+ T cells\",\n      \"pmids\": [\"25940347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct role of SYTL3 in Gag trafficking versus indirect effect not separated\",\n        \"No reconstitution of the implicated transport step\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mast cell studies showed the Rab27b/Slp3/kinesin-1 complex assembles in a PI3K-dependent manner upon IgE signaling, defining a signaling input that licenses motor recruitment and degranulation in vivo.\",\n      \"evidence\": \"Kif5b conditional knockout mice, BMMC degranulation, anaphylaxis model, Co-IP and PI3K inhibition\",\n      \"pmids\": [\"27810912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular target of PI3K signaling in complex assembly not identified\",\n        \"Direct contribution of endogenous SYTL3 loss-of-function not isolated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Knockdown and overexpression in bladder cancer cells established SYTL3 as a Rab27b effector mediating exocytosis of intracellular BCG, linking it to BCG therapy resistance.\",\n      \"evidence\": \"shRNA knockdown, overexpression, orthotopic xenograft and intracellular BCG quantification\",\n      \"pmids\": [\"32737155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of bacterial cargo recognition unknown\",\n        \"Single lab and cancer cell context\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Loss-of-function in human neurons and mouse cortex revealed SYTL3 restrains neuronal migration via matrix metalloproteinases and supports presynaptic release, extending its role beyond classical granule exocytosis.\",\n      \"evidence\": \"CRISPR knockout in hESC-derived neurons, in utero shRNA knockdown, brain organoids, MMP inhibitor and neurotransmitter release assays\",\n      \"pmids\": [\"33657377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Connection between Rab27/kinesin-1 trafficking role and MMP regulation unclear\",\n        \"Whether the C2/SHD domains mediate the migration phenotype untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pharmacological dissection in mast cells showed SYTL3 granule loading is independent of kinesin-1 motor recruitment, separating adaptor loading from motor engagement in the transport pathway.\",\n      \"evidence\": \"shRNA Kif5b knockdown, live imaging, granule fractionation and kinesore treatment\",\n      \"pmids\": [\"35316306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single biochemical method for the Slp3-specific result\",\n        \"Signal that triggers motor recruitment to pre-loaded adaptor not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the atypical C2A Ca2+/lipid-sensing module is integrated with Rab27/kinesin-1-driven transport to time and target granule fusion across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of the SYTL3/Rab27/kinesin-1 complex\",\n        \"Ca2+ sensing not linked to a defined fusion or docking step in vivo\",\n        \"Mechanism connecting trafficking role to MMP-dependent neuronal migration unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\n      \"Rab27a/Slp3/kinesin-1 transport complex\",\n      \"Rab27b/Slp3/kinesin-1 transport complex\"\n    ],\n    \"partners\": [\n      \"RAB27A\",\n      \"RAB27B\",\n      \"KLC1\",\n      \"KIF5B\",\n      \"NRXN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}