Affinage

SNX33

Sorting nexin-33 · UniProt Q8WV41

Length
574 aa
Mass
65.3 kDa
Annotated
2026-06-10
17 papers in source corpus 11 papers cited in narrative 12 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

SNX33 is a PX-BAR-SH3 sorting nexin that couples membrane remodeling to the control of endocytosis and actin dynamics across cytokinesis, phagosome maturation, macropinocytosis, and cell migration (PMID:18353773, PMID:21494661, PMID:22718350, PMID:37704612). Through its SH3 domain it binds the endocytic GTPase dynamin and reduces internalization of cell-surface cargo; for APP this dynamin-dependent retention at the plasma membrane shifts processing toward non-amyloidogenic alpha-secretase cleavage, increasing sAPPalpha and lowering Abeta, and the same surface-retention mechanism enhances shedding of full-length PrP and reduces PrP(Sc) formation (PMID:18353773, PMID:18419754). SNX33 homodimerizes specifically through its BAR domain rather than heterodimerizing with the related SNX9, a selectivity dictated by distinct residues at the BAR dimer interface (PMID:20964629). Its BAR domain is curvature-sensitive and locally inhibits actin polymerization at inwardly curved membrane regions of the leading edge, constraining migration speed and enabling obstacle evasion (PMID:37704612). SNX33 also drives actin-dependent membrane processes indirectly by binding the WASp VCA domain: it is required for cytokinesis, where its depletion causes multinucleation and disrupts MRLC(S19) localization and recruitment of Rab11 recycling endosomes to the intercellular bridge, and its overexpression elevates macropinosome formation (PMID:19487689, PMID:21048941, PMID:22718350). Functional conservation is demonstrated by the C. elegans ortholog LST-4, which acts downstream of dynamin (DYN-1) and upstream of RAB-5 in apoptotic corpse clearance and is rescued by mammalian SNX33 (PMID:21494661).

Mechanistic history

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

    Established the first molecular function of SNX33: that it restrains dynamin-dependent endocytosis to redirect APP toward alpha-secretase processing, linking a sorting nexin to amyloidogenic control.

    Evidence Expression cloning, dynamin co-immunoprecipitation, endocytosis rate assays, and dominant-negative dynamin comparison in cultured cells

    PMID:18353773

    Open questions at the time
    • Does not resolve whether SNX33 acts directly at APP-containing vesicles or globally on dynamin-dependent uptake
    • No structural basis for the SH3-dynamin interaction
  2. 2008 Medium

    Extended the surface-retention mechanism to a second cargo, showing SNX33 promotes PrP shedding and reduces prion conversion, indicating a general effect on plasma-membrane cargo trafficking.

    Evidence Overexpression, deletion mutant analysis, PrP shedding/endocytosis assays, and PrP(Sc) formation assay in cell lines

    PMID:18419754

    Open questions at the time
    • Relies on overexpression rather than endogenous loss-of-function
    • Mechanism of how reduced endocytosis lowers PrP(Sc) not directly tested
  3. 2009 Medium

    Connected SNX33 to actin machinery by identifying WASp as a binding partner and showing WASp knockdown rescues the cytokinesis defect, establishing an indirect actin-regulatory role.

    Evidence Co-immunoprecipitation, siRNA knockdown rescue/epistasis, and microscopy in HeLa and MCF7 cells

    PMID:19487689

    Open questions at the time
    • SNX33 does not bind actin directly, so intermediate steps remain undefined
    • Single lab; reciprocal validation of WASp interaction not described
  4. 2009 Medium

    Identified an isoform-specific SH3-mediated association with ADAM15, expanding the SNX33 interactome to a transmembrane sheddase.

    Evidence Co-precipitation from cell lysates with ADAM15 isoform mapping

    PMID:19718658

    Open questions at the time
    • Functional consequence of ADAM15 binding not established
    • Single co-precipitation method without reciprocal or in-vivo confirmation
  5. 2011 High

    Defined the structural determinants of SNX33 oligomerization, showing BAR-domain homodimerization with selectivity against SNX9 dictated by specific interface residues.

    Evidence Co-immunoprecipitation, domain deletion, domain-swap mutagenesis, and molecular modelling of the BAR domain

    PMID:20964629

    Open questions at the time
    • No high-resolution structure of the SNX33 dimer
    • Functional significance of homodimer-only behavior not directly tested in cells
  6. 2011 High

    Demonstrated evolutionary conservation and placed SNX33 in a dynamin-to-Rab5 axis for phagosome maturation during apoptotic corpse clearance.

    Evidence C. elegans lst-4 genetics, epistasis with DYN-1 and RAB-5, cross-species rescue by mammalian SNX33, and phagosome electron microscopy

    PMID:21494661

    Open questions at the time
    • Molecular mechanism linking SNX33 to RAB-5 activation not resolved
    • Whether mammalian SNX33 functions in phagosome maturation endogenously not shown
  7. 2012 High

    Resolved the cytokinetic role at the level of trafficking and contractile machinery, showing SNX33 is required for Rab11 endosome delivery and myosin light chain localization at the bridge.

    Evidence siRNA knockdown with time-lapse imaging, MRLC(S19) and Rab11 immunofluorescence, and transferrin endocytosis assay

    PMID:22718350

    Open questions at the time
    • Direct molecular targets of SNX33 at the abscission site not identified
    • Relationship between its endocytic and actin functions during cytokinesis unresolved
  8. 2019 Medium

    Placed SNX33 in a pharmacological pathway as the effector through which donepezil promotes non-amyloidogenic APP processing in neurons.

    Evidence Morpholino knockdown with cell-surface APP, sAPPalpha ELISA, and Abeta measurement in primary cortical neurons

    PMID:31417133

    Open questions at the time
    • How donepezil upregulates SNX33 expression is unknown
    • In-vivo relevance to amyloid pathology not established
  9. 2023 Medium

    Assigned a curvature-sensing function to the BAR domain in migration, showing SNX33 locally suppresses actin at inwardly curved leading-edge membrane to enable obstacle evasion.

    Evidence Genetic perturbation, live-cell imaging, and obstacle-evasion assays in immune-like migrating cells

    PMID:37704612

    Open questions at the time
    • Molecular link between curvature sensing and actin inhibition not defined
    • Whether WASp binding mediates this inhibition not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SNX33's two activities — SH3-dynamin-mediated endocytic regulation and BAR-domain curvature sensing coupled to WASp-dependent actin control — are integrated and selectively deployed across distinct membrane processes remains unresolved.
  • No unified model coupling endocytic and actin functions
  • No structural model of full-length SNX33 on membranes
  • Endogenous cargo repertoire beyond APP and PrP undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ADAM15DNM1SNX9WASP

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 SNX33 binds the endocytic GTPase dynamin and reduces the rate of APP endocytosis in a dynamin-dependent manner, thereby increasing APP at the plasma membrane and promoting alpha-secretase cleavage of APP. Exogenous SNX33 expression increased APP alpha-secretase cleavage ~4-fold, similar to the dominant-negative dynamin-1 K44A mutant. Expression cloning screen, co-immunoprecipitation of dynamin, endocytosis rate assays, dominant-negative dynamin comparison in cultured cells The Journal of biological chemistry High 18353773
2008 SNX33 overexpression in neuronal and non-neuronal cell lines increased shedding of full-length PrP from the plasma membrane and modulated the rate of PrP endocytosis, reducing PrP(Sc) formation in infected cells. Deletion mutant analysis showed that PrP fragment N1 production is not influenced by SNX33. Overexpression in cell lines, deletion mutant analysis, measurement of PrP shedding and endocytosis, PrP(Sc) formation assay Traffic (Copenhagen, Denmark) Medium 18419754
2009 SNX33 interacts with itself (homodimerizes), with SNX9, and with the VCA domain of Wiskott-Aldrich syndrome protein (WASp), mediating actin polymerization indirectly. Knockdown of WASp alleviates the cytokinesis-failure phenotype induced by SNX33 overexpression. SNX33 does not directly interact with actin. Co-immunoprecipitation, siRNA knockdown, cell lineage analysis, overexpression in HeLa and MCF7 cells The Journal of biological chemistry Medium 19487689
2009 Transient knockdown of SNX33 causes HeLa and MCF7 cells to grow multiple long processes, delays G1/M transition, and increases apoptosis. SNX33 overexpression causes cells to fail division and become micronucleated, with accumulation of actin at the perinuclear space, indicating a role in cytokinesis. siRNA knockdown, overexpression, cell cycle analysis, microscopy in HeLa/MCF7 cells The Journal of biological chemistry Medium 19487689
2010 Overexpression of SNX33 significantly elevates macropinosome formation in cultured cells (65.25 macropinosomes per 100 transfected cells vs. 24.44 in controls), though unlike SNX1, SNX5, SNX9, and SNX18, SNX33 does not associate with early-stage macropinosomes. Image-based screening, systematic overexpression, macropinosome quantification by microscopy PloS one Medium 21048941
2011 SNX33 forms homodimers via its BAR domain but not heterodimers with SNX9. The BAR domain (not the SH3 domain) is required for homodimerization. Key amino acids at the BAR domain dimer interface differ between SNX9 and SNX33; replacing these residues in SNX9 with corresponding SNX33 residues allowed heterodimerization, identifying molecular determinants of dimerization specificity. Co-immunoprecipitation, domain deletion analysis, domain swap experiments, molecular modelling of BAR domain structure The Biochemical journal High 20964629
2011 C. elegans SNX9-family member LST-4 (closest mammalian orthologue SNX33) functions in apoptotic cell corpse clearance downstream of DYN-1 and upstream of RAB-5 GTPase during phagosome maturation. Mammalian SNX33 rescues C. elegans lst-4 mutants, demonstrating functional conservation. Overexpression of truncated SNX33 fragments interfered with phagosome maturation in mammalian cells. C. elegans genetics (lst-4 mutants), genetic epistasis with DYN-1 and RAB-5, mammalian SNX33 rescue of C. elegans mutants, overexpression of truncated SNX33 in mammalian cells, electron microscopy of phagosomes PloS one High 21494661
2012 siRNA depletion of SNX33 induces multinucleation (cytokinesis failure) and accumulation of cytokinetic cells. Depletion disrupts MRLC(S19) localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge between nascent daughter cells. Endocytosis of transferrin is blocked during cytokinesis upon depletion of SNX33. siRNA knockdown, time-lapse microscopy, immunofluorescence for MRLC(S19) and Rab11, transferrin endocytosis assay Journal of cell science High 22718350
2009 SNX33 (a.k.a. SNX30) physically associates with specific ADAM15 isoforms (those containing the most carboxyterminal proline cluster) via SH3-domain binding, as demonstrated by co-precipitation from cell lysates. ADAM15 isoforms lacking this proline cluster do not associate with SNX33. Co-precipitation from cell lysates, domain/isoform analysis Journal of cellular biochemistry Medium 19718658
2015 Overexpression of SNX33 (mammalian ortholog of Drosophila Sh3px1) in Drosophila S2 cells generates long protrusions; formation of these structures requires the C-terminal BAR domain and the adjacent PX domain, as well as the actin nucleation factor Wasp. Overexpression in Drosophila S2 cells, domain deletion analysis, genetic requirement for Wasp Biology open Medium 26459243
2019 Donepezil increases SNX33 expression in primary cortical neurons, leading to decreased APP endocytosis, increased cell-surface APP, increased sAPPα secretion, and decreased Aβ. SNX33 knockdown (via morpholino antisense oligos) blocked all of donepezil's effects on APP processing, placing SNX33 downstream of donepezil and upstream of APP alpha-secretase cleavage. Morpholino knockdown, cell-surface APP measurement, sAPPα ELISA, Aβ measurement in primary cortical neurons Scientific reports Medium 31417133
2023 Snx33's curvature-sensitive BAR domain inhibits actin polymerization at the advancing edge of migrating cells in regions with inward plasma membrane curvature. Genetic perturbation of Snx33 reduces cells' capacity to evade obstacles and results in faster, more persistent migration in obstacle-free environments. Genetic perturbation (knockout/knockdown), live-cell imaging, obstacle evasion assays in immune-like migrating cells Nature communications Medium 37704612

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein. The Journal of biological chemistry 77 18353773
2010 The SNX-PX-BAR family in macropinocytosis: the regulation of macropinosome formation by SNX-PX-BAR proteins. PloS one 51 21048941
2012 SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis. Journal of cell science 33 22718350
2023 Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles. Nature communications 28 37704612
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
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
2019 Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons. Scientific reports 24 31417133
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
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
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
2025 A Feedback Loop Between Fatty Acid Metabolism and Epigenetics in Clear Cell Renal Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40391655
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
2020 COMMD8 changes expression during initial phase of wasp venom immunotherapy. The journal of gene medicine 2 32559011

Missed literature

Know a paper Affinage missed for SNX33? Flag it for the maintainers and the community.

No submissions yet.