Affinage

SNX18

Sorting nexin-18 · UniProt Q96RF0

Length
628 aa
Mass
68.9 kDa
Annotated
2026-06-10
25 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX18 is a PX-BAR sorting nexin that remodels endosomal membranes to drive membrane tubulation and carrier formation across multiple trafficking pathways (PMID:20427313, PMID:21969467). It directly binds dynamin and stimulates its basal GTPase activity, and also engages N-WASP and synaptojanin; SNX18 and SNX9 form a heterodimer and act redundantly in clathrin-mediated endocytosis, with SNX18 depletion impairing transferrin uptake (PMID:20427313). This redundant SNX9/SNX18 module supports clathrin-dependent internalization of diverse cargoes, including ADAM9 and the GPCRs CXCR4 (via a β-arrestin-independent route) and LPAR1 recycling (PMID:29622675, PMID:39511325, PMID:31668663). In autophagy, SNX18 acts downstream of the ATG14/class III PtdIns3K complex, directly binding LC3 and ATG16L1 and recruiting ATG16L1- and LC3-positive recycling endosomes to a perinuclear region to provide membrane for phagophore expansion; this pro-autophagic activity requires its membrane-binding and tubulation capacity and is negatively regulated by phosphorylation of S233 (PMID:23878278, PMID:24113029). SNX18 recruits Dynamin-2 to tubulate recycling endosomes and traffic ATG9A toward autophagosome precursor membranes (PMID:29437695). Beyond autophagy, SNX18 forms a complex with FIP5/Rab11 required for apical lumen formation (PMID:21969467), is required for cytokinesis (PMID:22718350), and its scaffolding of Dynamin-2 and N-WASP is exploited during Salmonella invasion (downstream of the effector SopB) and coupled to Notch ligand (Dll1) endocytosis via the Mib1 ubiquitin ligase (PMID:28664153, PMID:26923255).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Established SNX18 as a dynamin-activating BAR-domain protein functioning in clathrin-mediated endocytosis, defining its core biochemical activity and its relationship to SNX9.

    Evidence Co-IP, in vitro GTPase activity assay, shRNA knockdown, transferrin uptake, TIRF microscopy

    PMID:20427313

    Open questions at the time
    • Structural basis of dynamin GTPase stimulation not resolved
    • Division of labor versus full redundancy with SNX9 not delineated
  2. 2010 Medium

    Linked SNX18 to macropinosome formation, broadening its membrane-remodeling role beyond classical endocytosis.

    Evidence Systematic overexpression, image-based quantitation, co-expression with PTEN variants, live imaging

    PMID:21048941

    Open questions at the time
    • Based on overexpression rather than loss of function
    • PI(3,4,5)P3 dependence shown indirectly via PTEN co-expression
  3. 2011 High

    Showed SNX18 partners with FIP5/Rab11 to drive apical lumen formation, connecting its tubulation activity to polarized epithelial transport.

    Evidence Co-IP, siRNA knockdown, 3D lumen formation assay, membrane tubulation and lipid-binding assays

    PMID:21969467

    Open questions at the time
    • Specific apical cargoes trafficked not enumerated
    • Mechanism of FIP5-stimulated tubulation unresolved
  4. 2012 Medium

    Identified a requirement for SNX18 in cytokinesis, implicating recycling-endosome delivery to the intracellular bridge in cell division.

    Evidence siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay

    PMID:22718350

    Open questions at the time
    • Single-lab siRNA without genetic rescue
    • Direct molecular link between SNX18 and MRLC localization unclear
  5. 2013 High

    Defined SNX18 as a pro-autophagic factor that directly binds LC3 and ATG16L1 and supplies recycling-endosome-derived membrane to autophagosomes, with phospho-regulation at S233.

    Evidence siRNA screen, co-IP, live imaging, phosphosite mutagenesis, tubulation assays; epistasis with ATG14/class III PI3K

    PMID:23878278 PMID:24113029

    Open questions at the time
    • Kinase responsible for S233 phosphorylation not identified
    • How LC3/ATG16L1 binding is spatially coordinated with tubulation not resolved
  6. 2018 High

    Showed SNX18 recruits Dynamin-2 to mobilize ATG9A from recycling endosomes, mechanistically connecting its dynamin partnership to autophagosome precursor formation.

    Evidence SNX18 KO/KD, reciprocal co-IP, fluorescence microscopy, membrane tubulation assays

    PMID:29437695

    Open questions at the time
    • How ATG9A is selected as cargo not defined
    • Relationship between ATG9A and ATG16L1/LC3 membrane sources not fully integrated
  7. 2016 Medium

    Demonstrated that the Mib1 ubiquitin ligase tunes SNX18–Dynamin-2 interaction to drive Dll1 endocytosis, linking SNX18 to Notch signaling.

    Evidence Co-IP, ubiquitin-ligase activity mutants, Dll1 endocytosis assay, Notch reporter

    PMID:26923255

    Open questions at the time
    • Direct ubiquitination target not pinpointed
    • Single-lab finding without independent confirmation
  8. 2017 Medium

    Established SNX18 as a host scaffold hijacked during Salmonella invasion, recruiting Dynamin-2 and N-WASP via its SH3 domain downstream of the bacterial effector SopB.

    Evidence Overexpression/knockdown, PX-domain (R303Q) and ΔSH3 mutants, bacterial uptake quantification, microscopy

    PMID:28664153

    Open questions at the time
    • Phosphoinositide species recognized by PX domain in this context not specified
    • Single-lab study
  9. 2018 Medium

    Extended SNX9/SNX18 redundancy to ADAM9 internalization, reinforcing the heterodimer's general role in clathrin-dependent cargo uptake.

    Evidence Single and double siRNA knockdown, surface biotinylation, internalization assay

    PMID:29622675

    Open questions at the time
    • Direct binding of SNX18 to ADAM9 machinery not shown
    • Single-lab study
  10. 2019 Medium

    Connected SNX18-driven LPAR1 recycling to RhoA-mediated contractility and pancreatic cancer metastasis, demonstrating a disease-relevant trafficking loop.

    Evidence Knockdown, receptor recycling vs degradation assays, RhoA activation, traction force microscopy, in vivo metastasis

    PMID:31668663

    Open questions at the time
    • Whether SNX18 directly sorts LPAR1 or acts indirectly not resolved
    • Single-lab study
  11. 2024 Medium

    Defined SNX18 (with SNX9) as required for β-arrestin-independent CXCR4 endocytosis, distinguishing its trafficking route from canonical GPCR internalization.

    Evidence siRNA knockdown, receptor internalization assay, co-IP, comparison to β-arrestin depletion

    PMID:39511325

    Open questions at the time
    • Adaptor coupling SNX18 to CXCR4 not identified
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SNX18 cargo selectivity and pathway choice (endocytosis vs autophagy vs lumen formation vs cytokinesis) are coordinated, and what upstream signals beyond S233 phosphorylation govern its membrane-remodeling deployment.
  • No structural model integrating PX, BAR, and SH3 functions across pathways
  • Kinase/phosphatase network controlling S233 not mapped
  • Determinants of SNX9 vs SNX18 functional specialization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0008092 cytoskeletal protein binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 1
Partners
ATG16L1DNM2FIP5LC3MIB1N-WASPSNX9SYNAPTOJANIN
Complex memberships
FIP5-SNX18 complexSNX9-SNX18 heterodimer

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SNX18 directly interacts with LC3 and ATG16L1, promotes recruitment of ATG16L1-positive recycling endosomes to a perinuclear area, and delivers ATG16L1- and LC3-positive membranes to autophagosome precursors. Its pro-autophagic activity depends on membrane binding and tubulation capacity. Phosphorylation of S233 negatively regulates SNX18 membrane tubulation and autophagy function. siRNA screen, co-immunoprecipitation, live-cell imaging, phosphorylation-site mutagenesis, membrane tubulation assays The Journal of cell biology High 23878278
2013 SNX18 functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 interacts with ATG16L1 and LC3, facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes to provide membrane for phagophore expansion. siRNA knockdown, overexpression, genetic epistasis with ATG14/PI3K complex, fluorescence microscopy Autophagy High 24113029
2018 SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2. ATG9A accumulates in juxtanuclear recycling endosomes in SNX18-depleted cells. SNX18-Dynamin-2 binding is required for ATG9A trafficking from recycling endosomes and for formation of ATG16L1- and WIPI2-positive autophagosome precursor membranes. SNX18 knockout/knockdown, co-immunoprecipitation, fluorescence microscopy, membrane tubulation assays EMBO reports High 29437695
2010 SNX18 interacts with dynamin and stimulates its basal GTPase activity. SNX18 also interacts with N-WASP and synaptojanin. SNX18 and SNX9 form a heterodimer, colocalize in tubular membrane structures, and are functionally redundant in clathrin-mediated endocytosis at the plasma membrane. Depletion of SNX18 inhibits transferrin uptake. Co-immunoprecipitation, GTPase activity assay, shRNA knockdown, transferrin uptake assay, TIRF microscopy Journal of cell science High 20427313
2011 SNX18 directly interacts with FIP5 (a Rab11 GTPase binding protein); the FIP5-SNX18 complex is required for early apical lumen formation in epithelial cells. FIP5 promotes SNX18 membrane tubulation capacity, implicating the complex in endocytic carrier formation/scission during polarized transport of apical proteins. Co-immunoprecipitation, siRNA knockdown, 3D lumen formation assay, membrane tubulation assay, lipid-binding assay The Journal of cell biology High 21969467
2010 SNX18 overexpression significantly increases macropinosome formation and SNX18 associates with early-stage macropinosomes within 5 minutes of formation. The effect of SNX18 on macropinocytosis is synergistic with elevated PI(3,4,5)P3 levels. Systematic overexpression, image-based quantitation, co-expression with PTEN/PTEN(G129E), live-cell imaging PloS one Medium 21048941
2012 SNX18 is required for progression through and completion of mitosis, specifically the ingression and abscission stages of cytokinesis. Depletion of SNX18 induces multinucleation (cytokinesis failure), disrupts MRLC(S19) localization during ingression, and impairs recruitment of Rab11-positive recycling endosomes to the intracellular bridge. SNX18 depletion also blocks endocytosis of transferrin during cytokinesis. siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay Journal of cell science Medium 22718350
2017 During Salmonella invasion, SNX18 is recruited to bacteria-induced membrane ruffles and nascent Salmonella-containing vacuoles in a manner requiring the inositol-phosphatase activity of the bacterial effector SopB and an intact PX domain phosphoinositide-binding site in SNX18. SNX18 acts as a scaffold to recruit Dynamin-2 and N-WASP via its SH3 domain to promote Salmonella-containing vacuole formation and bacterial internalization. Overexpression and knockdown, phosphoinositide-binding mutant (R303Q), ΔSH3 mutant, bacteria uptake quantification, fluorescence microscopy Frontiers in cellular and infection microbiology Medium 28664153
2019 SNX18 and N-WASP cooperate to promote LPA receptor (LPAR1) recycling and prevent its degradation, thereby maintaining RhoA-mediated contractility and force generation in pancreatic cancer cells. This SNX18-dependent receptor recycling loop drives chemotaxis, collagen remodeling, and metastasis. Knockdown, receptor trafficking assay (recycling vs. degradation), RhoA activation assay, traction force microscopy, in vivo metastasis Developmental cell Medium 31668663
2016 Mib1 (an E3 ubiquitin ligase) promotes the interaction between Dynamin-2 and SNX18 in an ubiquitin-ligase-activity-dependent manner, thereby modulating Dynamin-2 recruitment to facilitate Dll1 (Notch ligand) endocytosis for efficient Notch signaling activation. Co-immunoprecipitation, ubiquitin ligase activity mutants, Dll1 endocytosis assay, Notch signaling reporter Genes to cells Medium 26923255
2010 SNX18 binds to the E3 ubiquitin ligase Itch via the SH3 domain of SNX18 and the proline-rich domain (PRD) of Itch, similarly to the related SNX9. Co-immunoprecipitation with truncated proteins The FEBS journal Low 20491914
2018 SNX18 (together with SNX9, redundantly) promotes ADAM9 internalization via clathrin-dependent endocytosis. Double knockdown of SNX9 and SNX18 significantly decreased ADAM9 internalization, demonstrating functional redundancy. siRNA knockdown (single and double), surface biotinylation, internalization assay The Journal of biological chemistry Medium 29622675
2015 HIV-1 Nef associates with SNX18, and this interaction is localized to AP-1-positive endosomal vesicles, as demonstrated by bimolecular fluorescence complementation during viral infection. Viral bimolecular fluorescence complementation (BiFC), co-localization imaging PloS one Low 25915798
2024 SNX18 (together with SNX9) is necessary for agonist-stimulated, β-arrestin-independent endocytosis of the chemokine receptor CXCR4. SNX9/SNX18 depletion blocks CXCR4 endocytosis, while β-arrestin depletion does not. siRNA knockdown, receptor internalization assay, co-immunoprecipitation Communications biology Medium 39511325
2011 SNX18 localizes dynamically to growth cones in developing spinal motor neurons and accumulates at areas of contact with permissive substrates, suggesting a role in membrane trafficking during axonal elongation. EGFP-SNX18 live-cell imaging, immunofluorescence in embryonic spinal cord The journal of histochemistry and cytochemistry Low 21339182
2025 MAP1LC3B recognizes SNX18 on the surface of endosome-escaped extracellular vesicles (EVs) to facilitate their sorting into the autolysosomal pathway for degradation. Mechanistic studies of EV degradation, SNX18 surface display, LC3-SNX18 interaction assays Cell chemical biology Low 41932333

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation. The Journal of cell biology 149 23878278
2014 Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease. The Journal of clinical investigation 91 24892806
2018 SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2. EMBO reports 80 29437695
2010 SNX18 shares a redundant role with SNX9 and modulates endocytic trafficking at the plasma membrane. Journal of cell science 57 20427313
2010 The SNX-PX-BAR family in macropinocytosis: the regulation of macropinosome formation by SNX-PX-BAR proteins. PloS one 51 21048941
2020 A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients. JCI insight 45 33108347
2011 Interaction between FIP5 and SNX18 regulates epithelial lumen formation. The Journal of cell biology 45 21969467
2019 N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis. Developmental cell 43 31668663
2012 SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis. Journal of cell science 33 22718350
2017 SopB-Mediated Recruitment of SNX18 Facilitates Salmonella Typhimurium Internalization by the Host Cell. Frontiers in cellular and infection microbiology 31 28664153
2013 SNX18 tubulates recycling endosomes for autophagosome biogenesis. Autophagy 27 24113029
2010 The E3 ubiquitin ligase Itch regulates sorting nexin 9 through an unconventional substrate recognition domain. The FEBS journal 21 20491914
2018 Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface. The Journal of biological chemistry 18 29622675
2015 Viral bimolecular fluorescence complementation: a novel tool to study intracellular vesicular trafficking pathways. PloS one 17 25915798
2016 Mib1 modulates dynamin 2 recruitment via Snx18 to promote Dll1 endocytosis for efficient Notch signaling. Genes to cells : devoted to molecular & cellular mechanisms 12 26923255
2015 Depletion or over-expression of Sh3px1 results in dramatic changes in cell morphology. Biology open 12 26459243
2011 Expression of sorting nexin 18 (SNX18) is dynamically regulated in developing spinal motor neurons. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 10 21339182
2020 Analysis of hepatic transcriptome modulation exerted by γ-conglutin from lupins in a streptozotocin-induced diabetes model. Gene 8 32777525
2023 Green Tea Polyphenols Alleviate Kidney Injury Induced by Di(2-Ethylhexyl) Phthalate in Mice. American journal of nephrology 7 37734331
2024 SNX9 family mediates βarrestin-independent GPCR endocytosis. Communications biology 6 39511325
2022 Transcriptome landscapes that signify Botrylloides leachi (Ascidiacea) torpor states. Developmental biology 4 35809632
2020 Genome-Wide Association Study of Sleep Disturbances in Depressive Disorders. Molecular neuropsychiatry 3 32399468
2026 A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway. Cell chemical biology 0 41932333
2025 Differences in Starvation-Induced Autophagy Response and miRNA Expression Between Rat Mammary Epithelial and Cancer Cells: Uncovering the Role of miR-218-5p. Cancers 0 40805149
2025 Insights into transcriptomic changes in blood of a mouse model of LPS-induced peritonitis. Toxicology and applied pharmacology 0 41173111

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