Affinage

SYTL3

Synaptotagmin-like protein 3 · UniProt Q4VX76

Length
610 aa
Mass
68.6 kDa
Annotated
2026-04-28
41 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYTL3 (Slp3) is a Rab27a/Rab27b effector that couples secretory granules and lysosomes to kinesin-1-dependent microtubule transport for regulated exocytosis across multiple cell types. Its N-terminal Slp homology domain (SHD) binds GTP-loaded Rab27a/b on granule membranes, while an adjacent region recruits kinesin-1 via the kinesin light chain TPR domain, forming a ternary Rab27–Slp3–kinesin-1 transport complex whose assembly in mast cells is PI3K-dependent (PMID:22308290, PMID:27810912, PMID:35316306). The C2A domain mediates Ca²⁺-dependent phospholipid binding through atypical residues (Glu-336/337) and a polybasic sequence, likely coordinating membrane docking (PMID:12049610). Beyond immune cell degranulation and CTL lytic granule secretion, SYTL3 restrains cortical neuronal migration—its loss accelerates migration via matrix metalloproteinase upregulation—and supports presynaptic neurotransmitter release (PMID:33657377).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 High

    Identification of SYTL3 as a synaptotagmin-like protein with Ca²⁺-dependent phospholipid-binding C2A domain established it as a candidate membrane-trafficking regulator distinct from Ca²⁺-independent family members.

    Evidence Subcellular fractionation and phospholipid binding assays on cloned Slp3

    PMID:11243866 PMID:11327731

    Open questions at the time
    • Physiological membrane target of the C2A domain unresolved
    • No in vivo functional data at this stage
    • Neurexin Iα binding not followed up in subsequent studies
  2. 2002 High

    Demonstration that the Slp3-a isoform promotes dense-core vesicle exocytosis in a Rab27A-binding-domain-dependent manner established SYTL3 as a functional Rab27A effector in regulated secretion, while mutagenesis of the C2A domain revealed an atypical Ca²⁺-binding mechanism.

    Evidence NPY secretion assay in PC12 cells with domain-deletion controls; site-directed mutagenesis of C2A Ca²⁺-binding residues with phospholipid binding assays

    PMID:12049610 PMID:12176990

    Open questions at the time
    • No endogenous loss-of-function validation in secretory cells
    • Relationship between C2A phospholipid binding and exocytosis not directly tested
    • Downstream molecular events after Rab27A engagement unknown
  3. 2012 High

    Discovery of the ternary Rab27a/Slp3/kinesin-1 complex revealed how SYTL3 physically bridges lytic granules to microtubule motors for terminal transport toward the immune synapse in CTLs.

    Evidence Reciprocal co-immunoprecipitation, dominant-negative inhibition, live-cell imaging, and secretion assays in CTLs

    PMID:22308290

    Open questions at the time
    • Structural basis of Slp3–kinesin light chain TPR interaction not resolved
    • Relative contributions of Slp3 versus Slp1/Slp2-a in CTL killing not fully dissected
    • Whether Slp3 recruits to granules before or after kinesin-1 engagement unclear
  4. 2015 Medium

    Co-expression rescue of Slp3 with Munc13-4 and Rab27a in Chediak-Higashi syndrome CTLs placed SYTL3 downstream of LYST in the lytic granule exocytosis pathway, and parallel work revealed Rab27a-effector-dependent trafficking of PI4KIIα endosomes needed for HIV-1 assembly.

    Evidence Overexpression rescue in patient CTLs with degranulation readout; Rab27a effector knockdown screen for HIV-1 Gag membrane association in CD4⁺ T cells

    PMID:25425525 PMID:25940347

    Open questions at the time
    • Slp3 contribution not isolated from co-expressed effectors in CHS rescue
    • Slp3 role not dissected separately from Slp2a/Slac2b in HIV assembly
    • Direct interaction between Slp3 and PI4KIIα not tested
  5. 2016 High

    Demonstration that PI3K activity upon FcεRI stimulation is required for Rab27b/Slp3/kinesin-1 complex formation in mast cells established a signaling-regulated assembly mechanism for the granule transport machinery, independent of microtubule reorganization.

    Evidence Kif5b knockout mice, co-immunoprecipitation, PI3K inhibitor treatment, mast cell degranulation and passive systemic anaphylaxis assays

    PMID:27810912

    Open questions at the time
    • PI3K substrate and direct phosphorylation target on Slp3 or kinesin-1 not identified
    • Whether PI3K regulation applies in CTLs or other cell types unknown
    • Mechanism switching between Rab27a and Rab27b engagement not clarified
  6. 2020 Medium

    Loss-of-function studies in bladder cancer cells showed Rab27b/SYTL3-mediated exocytosis expels BCG from urothelial cells, and knockdown enhanced intratumoral BCG retention and therapeutic efficacy in vivo.

    Evidence shRNA knockdown, BCG uptake/cytotoxicity assays, mouse orthotopic xenograft model

    PMID:32737155

    Open questions at the time
    • Specific vesicular compartment carrying BCG for Slp3-dependent exocytosis not characterized
    • Whether kinesin-1 is also required in this context not tested
    • Applicability beyond BCG therapy to general pathogen clearance unknown
  7. 2021 High

    SYTL3 knockout in human neurons and knockdown in mouse cortex revealed an unexpected role restraining neuronal migration via suppression of matrix metalloproteinases, and also demonstrated a requirement for presynaptic neurotransmitter release.

    Evidence CRISPR knockout in hESC-derived neurons, in utero electroporation in mouse cortex, brain organoids, neurotransmitter release and MMP expression analysis

    PMID:33657377

    Open questions at the time
    • How Slp3 loss leads to MMP upregulation mechanistically is unclear
    • Rab27 isoform specificity in neuronal migration not addressed
    • Whether the presynaptic role involves the kinesin-1 transport complex is untested
  8. 2022 Medium

    Biochemical fractionation showed Slp3 recruitment to mast cell granules is independent of kinesin-1 association, establishing that cargo adaptor loading precedes motor engagement.

    Evidence Kif5b shRNA knockdown combined with granule fractionation and kinesore treatment in mast cells

    PMID:35316306

    Open questions at the time
    • What recruits Slp3 to granules upstream of motor attachment is not identified
    • Whether Rab27b activation alone is sufficient for granule recruitment not tested
    • Temporal sequence of Slp3 recruitment relative to PI3K activation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the Slp3–kinesin light chain interaction, the identity of the PI3K effector that licenses ternary complex assembly, how Slp3 loss upregulates MMPs in neurons, and whether Slp3-mediated transport is functionally redundant with Slp1/Slp2-a across tissue contexts.
  • No structural data for Slp3 or its complexes
  • PI3K substrate linking signaling to complex assembly unidentified
  • Mechanism connecting Slp3 to MMP transcription or secretion in neurons unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2
Localization
GO:0031410 cytoplasmic vesicle 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-168256 Immune System 2 R-HSA-112316 Neuronal System 1
Partners
KIF5BKLC1RAB27ARAB27B
Complex memberships
Rab27/Slp3/kinesin-1 transport complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SYTL3 (Slp3) was identified as a novel member of the synaptotagmin-like protein family with C-terminal tandem C2 domains. Subcellular fractionation showed Slp3 is a peripheral membrane protein. The Slp3 C2A domain exhibits Ca2+-dependent phospholipid-binding activity, distinguishing it from Slp1 and Slp2 which are Ca2+-independent isoforms. The C-terminus of Slp1-3 bound neurexin Iα in vitro. Subcellular fractionation, phospholipid binding assay, in vitro binding assay Biochemical and biophysical research communications High 11243866
2001 Alternative splicing isoforms of Slp3 (Slp3-a and Slp3-b) were identified. The N-terminal domains of Slp family members contain two conserved regions (SHD1 and SHD2), which may function as protein interaction sites. In Slp3-a and Slp4, SHD1 and SHD2 are separated by a putative Zn2+-binding sequence. Molecular cloning, sequence alignment Biochemical and biophysical research communications Medium 11327731
2002 Expression of Slp3-a (but not Slp3-b, which lacks the N-terminal Rab27A-binding domain) promotes neuropeptide Y (NPY) secretion in PC12 cells, establishing that Slp3-a regulates dense-core vesicle exocytosis via binding to Rab27A. Overexpression in PC12 cells, NPY secretion assay The Journal of biological chemistry High 12176990
2002 The C2A domain of Slp3 exhibits Ca2+-dependent phospholipid-binding activity. Site-directed mutagenesis identified Glu-336, Glu-337 in the putative Ca2+-binding loop 1 and a polybasic sequence (Lys-359, Lys-360, Lys-361) in the β-4 strand as crucial for this activity. This mechanism differs from other C-type tandem C2 proteins that require five conserved acidic residues. In vitro phospholipid binding assay, site-directed mutagenesis, chimeric domain analysis The Biochemical journal High 12049610
2008 Slp3-a (SYTL3) is expressed in cytotoxic T lymphocytes (CTLs) at low levels. Slp1 and Slp2-a (but not Slp3-a) were found to localize predominantly to the plasma membrane of CTLs and interact with Rab27a. Overexpression of a dominant-negative SHD of Slp2-a (56% identical to Slp1 SHD) reduces target cell killing, suggesting Slp family members contribute to secretory lysosome exocytosis at the immunological synapse. Expression screening, Co-immunoprecipitation, localization by microscopy, dominant-negative overexpression, cytotoxicity assay Traffic (Copenhagen, Denmark) Medium 18266782
2012 SYTL3 (Slp3) was identified as a Rab27a effector in cytotoxic T lymphocytes that interacts with kinesin-1 through the tetratricopeptide repeat (TPR) of the kinesin-1 light chain. The Rab27a/Slp3/kinesin-1 transport complex mediates terminal transport of lytic granules toward the immune synapse along microtubules. Inhibition of this complex impairs lytic granule secretion. Co-immunoprecipitation, dominant-negative inhibition, live-cell imaging, secretion assays Blood High 22308290
2015 Increasing expression of Slp3 (along with Munc13-4 and Rab27a) in Chediak-Higashi syndrome CTLs (LYST-deficient) restores cytotoxic granule dynamics and secretory ability at the immunological synapse, placing Slp3 downstream of LYST in the lytic granule exocytosis pathway. Overexpression rescue experiment in patient CTLs, confocal microscopy, degranulation assay Traffic (Copenhagen, Denmark) Medium 25425525
2015 Slp3 (along with Slp2a and Slac2b) is required for association of HIV-1 Pr55(Gag) with the plasma membrane in CD4+ T cells; this occurs via Rab27a-dependent trafficking of PI4KIIα-positive endosomes to the plasma membrane, controlling PI(4,5)P2 production needed for viral assembly. Rab27a effector screening, knockdown with functional readout (Gag membrane association), confocal microscopy The Journal of cell biology Medium 25940347
2016 In mast cells, SYTL3 (Slp3) functions as the critical effector linking kinesin-1 to Rab27b-associated secretory granules. The kinesin-1/Slp3/Rab27b complex formation is dependent on PI3K activity upon FcεRI stimulation, is independent of microtubule reorganization, and is required for microtubule-dependent movement of secretory granules for degranulation and anaphylaxis. Kif5b knockout mouse model, Co-immunoprecipitation, PI3K inhibitor treatment, bone marrow-derived mast cell degranulation assay, passive systemic anaphylaxis model The Journal of cell biology High 27810912
2020 SYTL3 knockdown in bladder cancer cells increases intracellular BCG quantity and BCG cytotoxicity, suggesting that Rab27b/SYTL3-mediated exocytosis drives BCG elimination from urothelial cells. Knockdown of SYTL3 or Rab27b in a mouse orthotopic xenograft model enhanced BCG accumulation within tumors and suppressed tumor growth. shRNA knockdown, in vitro BCG uptake/cytotoxicity assay, mouse orthotopic xenograft model Molecular cancer therapeutics Medium 32737155
2021 SYTL3 knockout in human neurons or Sytl3 knockdown in embryonic mouse cortex accelerates neuronal migration. SYTL3-KO causes abnormal distribution of deep-layer neurons in brain organoids, reduces presynaptic neurotransmitter release in hESC-derived neurons, and the accelerated migration phenotype is modulated by upregulation of matrix metalloproteinases. CRISPR knockout in hESC-derived neurons, in utero electroporation knockdown in mouse cortex, brain organoids, neurotransmitter release assay, MMP expression analysis Cell reports High 33657377
2022 In mast cells, Slp3 serves as a granule cargo adaptor for kinesin-1; shRNA knockdown of Kif5b reduced exocytosis but did not affect Slp3 levels in the granule-enriched fraction, indicating that cargo adaptor (Slp3) recruitment to granules is independent of motor association. shRNA knockdown of Kif5b, biochemical granule fractionation, kinesore pharmacological treatment, live-cell imaging PloS one Medium 35316306

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1983 Plasmids, recombination and chromosome mapping in Streptomyces lividans 66. Journal of general microbiology 381 6631413
2001 Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice. Proceedings of the National Academy of Sciences of the United States of America 209 11504925
2006 A stomatin-domain protein essential for touch sensation in the mouse. Nature 205 17167420
2012 Terminal transport of lytic granules to the immune synapse is mediated by the kinesin-1/Slp3/Rab27a complex. Blood 93 22308290
2001 Synaptotagmin-like protein 1-3: a novel family of C-terminal-type tandem C2 proteins. Biochemical and biophysical research communications 90 11243866
2013 The genome sequence of Streptomyces lividans 66 reveals a novel tRNA-dependent peptide biosynthetic system within a metal-related genomic island. Genome biology and evolution 86 23709624
2011 Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting. Proceedings of the National Academy of Sciences of the United States of America 85 21646512
2008 Slp1 and Slp2-a localize to the plasma membrane of CTL and contribute to secretion from the immunological synapse. Traffic (Copenhagen, Denmark) 78 18266782
2001 Novel splicing isoforms of synaptotagmin-like proteins 2 and 3: identification of the Slp homology domain. Biochemical and biophysical research communications 75 11327731
2002 Slp4-a/granuphilin-a regulates dense-core vesicle exocytosis in PC12 cells. The Journal of biological chemistry 71 12176990
2015 Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate. The Journal of cell biology 68 25940347
1992 Cloning and DNA sequence analysis of the mercury resistance genes of Streptomyces lividans. Molecular & general genetics : MGG 61 1494353
2015 LYST controls the biogenesis of the endosomal compartment required for secretory lysosome function. Traffic (Copenhagen, Denmark) 59 25425525
2012 Genome-wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus. PloS one 45 23082221
2002 Cloning and characterization of SLP3: a novel member of the stomatin family expressed by olfactory receptor neurons. Journal of the Association for Research in Otolaryngology : JARO 39 12239636
2016 Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex. The Journal of cell biology 37 27810912
2019 Identification of hub genes and key pathways associated with the progression of gynecological cancer. Oncology letters 35 31788113
2008 Slipins: ancient origin, duplication and diversification of the stomatin protein family. BMC evolutionary biology 35 18267007
2013 Evolution of bacterial-like phosphoprotein phosphatases in photosynthetic eukaryotes features ancestral mitochondrial or archaeal origin and possible lateral gene transfer. Plant physiology 32 24108212
2017 Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas. The Journal of clinical endocrinology and metabolism 31 27854551
2002 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. The Biochemical journal 31 12049610
2003 Expression of subtilisin-like serine proteases in Arabidopsis thaliana is cell-specific and responds to jasmonic acid and heavy metals with developmental differences. Physiologia plantarum 30 12702015
2020 Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis. Molecular cancer therapeutics 26 32737155
2009 A single conserved proline residue determines the membrane topology of stomatin. The Biochemical journal 22 19032151
2012 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. Atherosclerosis 21 22361517
2023 Coordinated reprogramming of renal cancer transcriptome, metabolome and secretome associates with immune tumor infiltration. Cancer cell international 16 36604669
2020 SPT20 Regulates the Hog1-MAPK Pathway and Is Involved in Candida albicans Response to Hyperosmotic Stress. Frontiers in microbiology 14 32153525
2018 The Candida albicans stress response gene Stomatin-Like Protein 3 is implicated in ROS-induced apoptotic-like death of yeast phase cells. PloS one 14 29389961
2022 Mast cell granule motility and exocytosis is driven by dynamic microtubule formation and kinesin-1 motor function. PloS one 13 35316306
2016 Characterization of Three Different Unusual S-Layer Proteins from Viridibacillus arvi JG-B58 That Exhibits Two Super-Imposed S-Layer Proteins. PloS one 10 27285458
2021 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. Frontiers in cardiovascular medicine 9 34458338
2023 Cell Protection and Crystal Endocytosis Inhibition by Sulfated Laminaria Polysaccharides Against Nano-COM-Induced Oxidative Damage in Renal Epithelial Cells. ACS omega 8 36872978
2020 The Search for Molecular Markers in a Gene-Orphan Case Study of a Pediatric Spinal Cord Pilocytic Astrocytoma. Cancer genomics & proteomics 8 32108034
2023 Identification of candidate genomic regions for egg yolk moisture content based on a genome-wide association study. BMC genomics 7 36918797
2021 Transcriptional networks identify synaptotagmin-like 3 as a regulator of cortical neuronal migration during early neurodevelopment. Cell reports 7 33657377
2021 SYTL3-SLC22A3 Single-Nucleotide Polymorphisms and Gene-Gene/Environment Interactions on the Risk of Hyperlipidemia. Frontiers in genetics 7 34367243
2023 Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis. Biomedicines 5 38001974
2024 Mitochondrial targeting of Candida albicans SPFH proteins and requirement of stomatins for SDS-induced stress tolerance. Microbiology spectrum 2 39641539
2024 Different Degrees of Sulfated Laminaria Polysaccharides Recovered Damaged HK-2 Cells and Inhibited Adhesion of Nano-COM and Nano-COD Crystals. Bioinorganic chemistry and applications 1 38204734
2023 Genome-wide analysis of circRNA regulation during spleen development of Chinese indigenous breed Meishan pigs. BMC genomics 1 37612620
2025 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. Frontiers in immunology 0 40963613