Affinage

SNX33

Sorting nexin-33 · UniProt Q8WV41

Round 2 corrected
Length
574 aa
Mass
65.3 kDa
Annotated
2026-04-28
57 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX33 is a BAR-PX-SH3 domain-containing sorting nexin that regulates endocytosis, actin dynamics, and membrane trafficking to control substrate availability at the plasma membrane, cell division, and directed cell migration. Through its SH3 domain, SNX33 binds dynamin and WASp, reducing the endocytic rate of transmembrane substrates such as APP and PrP and thereby promoting their alpha-secretase-mediated shedding at the cell surface (PMID:18353773, PMID:18419754). SNX33 homodimerizes via its BAR domain—but does not heterodimerize with SNX9—and is required, together with SNX9 and SNX18, for cytokinesis completion through endocytosis-dependent recruitment of Rab11-positive recycling endosomes and proper MRLC localization at the intracellular bridge (PMID:20964629, PMID:22718350). SNX33 also functions as a curvature-sensitive inhibitor of actin polymerization at the leading edge of migrating cells, enabling obstacle evasion during directed migration (PMID:37704612).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 High

    Identification of SNX33 as an endocytic regulator that modulates alpha-secretase processing of APP by binding dynamin and slowing APP internalization established its core mechanism: controlling substrate residence time at the plasma membrane.

    Evidence Expression cloning screen, co-IP of SNX33–dynamin, endocytosis rate assays, and dominant-negative dynamin comparison in mammalian cell lines

    PMID:18353773

    Open questions at the time
    • Direct binding stoichiometry and affinity between SNX33 SH3 domain and dynamin not measured
    • Whether SNX33 affects APP processing in neurons in vivo not addressed
  2. 2008 Medium

    Extension of the endocytic-regulation paradigm to prion protein showed SNX33's effect is not APP-specific: overexpression increased PrP shedding and reduced PrPSc formation, broadening SNX33's substrate scope.

    Evidence Overexpression in neuronal and non-neuronal cell lines, deletion mutant analysis, PrPSc formation assay

    PMID:18419754

    Open questions at the time
    • Only overexpression tested; loss-of-function data for PrP processing absent
    • Whether SNX33 directly binds PrP or acts solely via dynamin not resolved
  3. 2009 Medium

    Discovery that SNX33 binds WASp and that WASp knockdown rescues SNX33-induced cytokinesis failure placed SNX33 upstream of WASp-dependent actin polymerization, revealing a second effector axis beyond dynamin.

    Evidence Co-IP of SNX33–WASp VCA domain, siRNA epistasis, time-lapse microscopy, flow cytometry

    PMID:19487689

    Open questions at the time
    • In vitro reconstitution of SNX33–WASp interaction not performed
    • Relative contributions of WASp and dynamin to SNX33-dependent phenotypes not dissected
  4. 2011 High

    Structural analysis of the BAR domain demonstrated that SNX33 homodimerizes but cannot heterodimerize with SNX9, with non-conserved residues at the dimer interface dictating specificity—explaining functional non-redundancy within the SNX9 subfamily.

    Evidence Co-IP, domain deletion and swap mutagenesis, molecular modeling of BAR domain interface

    PMID:20964629

    Open questions at the time
    • Crystal structure of the SNX33 BAR domain not solved
    • Whether homodimerization is required for each of SNX33's distinct functions not tested
  5. 2011 High

    Cross-species rescue of C. elegans lst-4 mutants by mammalian SNX33 and genetic epistasis placing lst-4/SNX33 at the same step as dynamin upstream of RAB-5 demonstrated evolutionarily conserved function in phagosome maturation during apoptotic cell clearance.

    Evidence C. elegans double-mutant epistasis, cross-species rescue, truncated domain expression in mammalian cells, EM

    PMID:21494661

    Open questions at the time
    • Whether mammalian SNX33 participates in apoptotic cell clearance in vivo in vertebrates not shown
    • Mechanism by which SNX33 promotes RAB-5 recruitment not defined
  6. 2012 High

    Depletion of SNX33 (and SNX9/SNX18) caused cytokinesis failure with disrupted MRLC localization and Rab11-recycling-endosome recruitment to the intracellular bridge, establishing that SNX9-family-dependent endocytosis is required for abscission.

    Evidence siRNA knockdown, time-lapse imaging, immunofluorescence for MRLC and Rab11, transferrin endocytosis assay during cytokinesis

    PMID:22718350

    Open questions at the time
    • Individual contribution of SNX33 versus SNX9/SNX18 to cytokinesis not fully resolved
    • Whether the endocytic cargo critical for abscission has been identified
  7. 2014 Medium

    Identification of ADAM15 as an SH3-domain-dependent interaction partner revealed that alternative splicing of a substrate's cytoplasmic tail gates its interaction with SNX33, adding a selectivity mechanism for SNX33-regulated trafficking.

    Evidence Co-precipitation with ADAM15 isoform panel from cell lysates

    PMID:19718658

    Open questions at the time
    • Functional consequence of SNX33–ADAM15 interaction on ADAM15 trafficking or shedding not tested
    • No in vitro reconstitution of direct binding
  8. 2019 Medium

    Demonstration that donepezil promotes non-amyloidogenic APP processing through SNX33 upregulation in primary cortical neurons provided a pharmacological validation of the SNX33–endocytosis–alpha-secretase axis in a disease-relevant system.

    Evidence Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA for sAPPα and Aβ, surface biotinylation

    PMID:31417133

    Open questions at the time
    • In vivo validation in animal models not provided
    • Mechanism by which donepezil upregulates SNX33 expression unknown
  9. 2023 Medium

    Identification of SNX33 as a curvature-sensitive inhibitor of actin polymerization at the leading edge reframed the protein as a mechanosensory regulator: SNX33 loss increased migration speed but impaired obstacle evasion, linking membrane curvature sensing to steering decisions.

    Evidence Genetic knockout/knockdown, live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis

    PMID:37704612

    Open questions at the time
    • Direct measurement of SNX33 BAR domain curvature preference not reported
    • Whether SNX33-mediated actin inhibition acts through WASp or a distinct effector not resolved
    • In vivo migration phenotype not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which SNX33 integrates its dual roles—dynamin-dependent endocytic regulation and curvature-dependent actin inhibition—in the same cell, and whether these represent a unified membrane-remodeling activity, remains unresolved.
  • No structural data for SNX33 BAR or full-length protein
  • Relative importance of homodimerization for endocytic versus actin-regulatory functions untested
  • No unbiased interactome or proximity-labeling study reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM15DNM1DNM2RAB11ASNX9WASL

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 SNX33 was identified as a new activator of APP alpha-secretase cleavage. Exogenous SNX33 expression increased APP alpha-secretase cleavage ~4-fold, with little effect on beta-secretase cleavage. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner, increasing APP at the plasma membrane where alpha-secretase cleavage predominantly occurs. Expression cloning screen, co-immunoprecipitation (dynamin binding), endocytosis assays, dominant-negative dynamin comparison The Journal of biological chemistry High 18353773
2008 SNX33 overexpression in neuronal and non-neuronal cell lines increased shedding of full-length PrP(c) from the plasma membrane and modulated the rate of PrP(c) endocytosis. Using deletion mutants, production of PrP fragment N1 was not influenced by SNX33. Increased PrP shedding was paralleled by reduction of PrP(Sc) formation in persistently and newly infected cells. Overexpression in cell lines, deletion mutant analysis, endocytosis rate assay, PrPSc formation assay Traffic (Copenhagen, Denmark) Medium 18419754
2009 SNX33 interacts with itself (homodimerization) and with SNX9, and binds the VCA domain of Wiskott-Aldrich syndrome protein (WASp). SNX33 overexpression induced perinuclear actin accumulation and cytokinesis failure (micronucleation); knockdown caused multinucleation, G1/M delay, and apoptosis. WASp knockdown alleviated the cytokinesis defect induced by SNX33 overexpression, placing SNX33 upstream of WASp in actin polymerization. Co-immunoprecipitation (SNX33-SNX9, SNX33-WASp VCA domain), siRNA knockdown, overexpression, time-lapse microscopy, flow cytometry cell cycle analysis The Journal of biological chemistry Medium 19487689
2010 Overexpression of SNX33 significantly elevated macropinosome formation (65.25 ± 6.95 macropinosomes per 100 transfected cells vs. 24.44 ± 1.81 for controls), implicating SNX33 in macropinocytosis regulation. Unlike SNX1, SNX5, SNX9, and SNX18, SNX33 did not associate with early-stage macropinosomes. Image-based screening, systematic overexpression, quantitative macropinosome counting PloS one Medium 21048941
2011 SNX33 forms homodimers but not heterodimers with other BAR domain-containing proteins such as SNX9. The BAR domain (not the SH3 domain) is required for SNX33 homodimerization and prevents heterodimerization with SNX9. Molecular modeling of the SNX33 BAR domain identified key non-conserved amino acids at the dimer interface; replacing these residues in SNX9 with corresponding SNX33 residues enabled SNX9 to heterodimerize with SNX33. Co-immunoprecipitation, domain deletion analysis, domain swap experiments, molecular modeling The Biochemical journal High 20964629
2011 C. elegans LST-4, the SNX9-family ortholog of mammalian SNX33, functions at the same genetic step as DYN-1 (dynamin) during apoptotic cell corpse clearance, upstream of RAB-5. Mammalian SNX33 rescued C. elegans lst-4 mutants, and truncated SNX33 fragments interfered with phagosome maturation in mammalian cells, demonstrating evolutionary conservation of function in apoptotic phagosome maturation. C. elegans genetic epistasis (lst-4/dyn-1/rab-5 double mutants), cross-species rescue, truncated domain overexpression in mammalian cells, electron microscopy PloS one High 21494661
2012 SNX33 (along with SNX9 and SNX18) is required for progression through and completion of mitosis. siRNA depletion of SNX33 induced multinucleation (cytokinesis failure) and accumulation of cytokinetic cells. Depletion disrupted MRLC(S19) localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge. Endocytosis of transferrin was blocked during cytokinesis upon SNX33 depletion, suggesting an endocytosis-dependent role in cytokinesis. siRNA knockdown, time-lapse microscopy, immunofluorescence (MRLC, Rab11), transferrin endocytosis assay Journal of cell science High 22718350
2014 SNX33 interacts with ADAM15 isoforms via SH3 domain binding to a proline-rich region in the ADAM15 cytoplasmic tail. Robust cellular co-precipitation with SNX33 was observed only for ADAM15 isoforms containing the most carboxyterminal proline cluster (absent in isoforms i1 and i3), demonstrating that alternative splicing of ADAM15 regulates its interaction with SNX33. Co-precipitation from cell lysates, ADAM15 isoform panel analysis Journal of cellular biochemistry Medium 19718658
2019 Donepezil treatment upregulates SNX33 expression in primary cortical neurons, leading to increased APP surface expression, elevated sAPPα secretion, and reduced amyloid β levels. SNX33 knockdown by morpholino oligos prevented all effects of donepezil on APP processing, demonstrating that donepezil acts through SNX33 to decrease APP endocytosis and promote non-amyloidogenic α-secretase cleavage. Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA (sAPPα, Aβ), surface biotinylation of APP, Western blotting Scientific reports Medium 31417133
2023 SNX33 (Snx33) acts as a curvature-sensitive BAR domain protein that inhibits actin polymerization at the advancing edge of migrating cells in regions with inward plasma membrane curvature. Genetic perturbation of Snx33 reduced the cells' capacity to evade obstacles while increasing migration speed and persistence in obstacle-free environments, establishing Snx33 as a mechanosensory regulator of directed cell migration. Genetic perturbation (knockout/knockdown), live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis Nature communications Medium 37704612

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2006 The Phox (PX) domain proteins and membrane traffic. Biochimica et biophysica acta 160 16782399
2012 Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. The EMBO journal 152 23085988
2015 Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes. Molecular systems biology 120 25609649
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2006 Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome. EMBO reports 99 16374509
2018 Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function. EMBO reports 92 29467282
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2008 A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein. The Journal of biological chemistry 76 18353773
2020 Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease. Translational neurodegeneration 52 32552912
2010 The SNX-PX-BAR family in macropinocytosis: the regulation of macropinosome formation by SNX-PX-BAR proteins. PloS one 51 21048941
2022 Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease. Diabetologia 49 35763030
2015 Quantitative Proteomics Reveals Dynamic Interactions of the Minichromosome Maintenance Complex (MCM) in the Cellular Response to Etoposide Induced DNA Damage. Molecular & cellular proteomics : MCP 44 25963833
2016 Gsk3β and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. The Biochemical journal 41 27503909
2022 A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins. Viruses 37 35337019
2020 A heterodimeric SNX4--SNX7 SNX-BAR autophagy complex coordinates ATG9A trafficking for efficient autophagosome assembly. Journal of cell science 37 32513819
2012 SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis. Journal of cell science 33 22718350
2023 Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity. Molecular cell 27 36736316
2009 Sorting nexin 33 induces mammalian cell micronucleated phenotype and actin polymerization by interacting with Wiskott-Aldrich syndrome protein. The Journal of biological chemistry 27 19487689
2023 Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles. Nature communications 26 37704612
2011 A conserved role for SNX9-family members in the regulation of phagosome maturation during engulfment of apoptotic cells. PloS one 26 21494661
2008 The novel sorting nexin SNX33 interferes with cellular PrP formation by modulation of PrP shedding. Traffic (Copenhagen, Denmark) 26 18419754
2023 TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing. Neuro-oncology 25 36215168
2015 Preferred SH3 domain partners of ADAM metalloproteases include shared and ADAM-specific SH3 interactions. PloS one 25 25825872
2021 Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study. eLife 24 34515027
2019 Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons. Scientific reports 23 31417133
2022 HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation. Cellular and molecular gastroenterology and hepatology 19 36244648
2025 Multimodal cell maps as a foundation for structural and functional genomics. Nature 18 40205054
2023 CRISPR-based screening identifies XPO7 as a positive regulator of senescence. Protein & cell 18 36897256
2011 Specific amino acids in the BAR domain allow homodimerization and prevent heterodimerization of sorting nexin 33. The Biochemical journal 18 20964629
2009 Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins. Journal of cellular biochemistry 18 19718658
2009 Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening. BMC immunology 18 19807924
2019 Distinct Patterns of mRNA and lncRNA Expression Differences Between Lung Squamous Cell Carcinoma and Adenocarcinoma. Journal of computational biology : a journal of computational molecular cell biology 17 31750732
2022 Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis. Cell reports 12 36543142
2015 Depletion or over-expression of Sh3px1 results in dramatic changes in cell morphology. Biology open 12 26459243
2011 Reconciling gene trees of eastern North American minnows. Molecular phylogenetics and evolution 7 21669293
2025 Transcriptomic Signatures in TP53 Positive and Negative Tumor Samples in NSCLC. Current gene therapy 5 40798960
2023 Identifying novel regulatory effects for clinically relevant genes through the study of the Greek population. BMC genomics 5 37543566
2018 Molecular phylogeny of Banjo catfishes (Ostaryophisi: Siluriformes: Aspredinidae): A continental radiation in South American freshwaters. Molecular phylogenetics and evolution 5 29723648
2021 [Donepezil Reduces Amyloid Precursor Protein Endocytosis by Resulting from Increase in the Expression of Sorting Nexin Protein 33]. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 3 34078793
2025 A Feedback Loop Between Fatty Acid Metabolism and Epigenetics in Clear Cell Renal Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40391655
2020 COMMD8 changes expression during initial phase of wasp venom immunotherapy. The journal of gene medicine 2 32559011
2026 Integrated miRNA-proteomic profiling identifies chronic vesicle-trafficking and proteostasis disruptions after mild traumatic brain injury. Experimental neurology 0 41605412
2025 SNX30 inhibits lung adenocarcinoma cell proliferation and induces cell ferroptosis through regulating SETDB1. Journal of cardiothoracic surgery 0 39780196
2025 Anthraquinone-2-Carboxylic Acid Is a Potential Antiviral Candidate Against Influenza Viruses In Vitro and In Vivo. Viruses 0 40431640
2025 Susceptibility and protective genes in diabetic retinopathy: A comprehensive single-cell RNA sequencing analysis. Experimental eye research 0 41076048