Affinage

SNX6

Sorting nexin-6 · UniProt Q9UNH7

Round 2 corrected
Length
406 aa
Mass
46.6 kDa
Annotated
2026-04-28
39 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX6 is a PX-BAR domain sorting nexin that functions as a core subunit of the ESCPE-1 membrane-deforming complex (heterodimerizing with SNX1 or SNX2) within the retromer pathway, mediating endosome-to-TGN retrograde retrieval of cation-independent mannose-6-phosphate receptor (CI-MPR) (PMID:17148574, PMID:29908913). SNX6 recruits the dynein/dynactin motor complex to retromer-associated endosomal tubules through direct interaction with p150(Glued), coupling cargo sorting to microtubule-based transport required for tubulovesicular carrier formation and detachment (PMID:19935774, PMID:19619496). In hippocampal neurons, SNX6 operates independently of canonical retromer to regulate postsynaptic Homer1b/c distribution in dendrites and to sort newly synthesized GluA2 AMPA receptor subunits into the post-Golgi secretory pathway; loss of neuronal SNX6 diverts GluA2 to lysosomal degradation, reduces surface AMPAR levels, impairs LTP, and causes spatial learning and memory deficits (PMID:28134614, PMID:41429886).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2001 Medium

    Identification of SNX6 as a sorting nexin that forms heteromeric complexes with SNX1/SNX2 and localizes to early endosomes established the molecular context for its subsequent role in endosomal sorting.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and GFP-confocal colocalization with EEA1 in HeLa cells

    PMID:11279102 PMID:11485546

    Open questions at the time
    • No cargo or trafficking phenotype identified at this stage
    • Receptor interactions (TGF-β family) not functionally validated in a trafficking assay
    • Stoichiometry and domain contributions to SNX heteromeric complexes undefined
  2. 2006 High

    An RNAi screen demonstrated that SNX6 (together with SNX5) is required for retromer-mediated endosome-to-TGN retrieval of CI-MPR, establishing SNX6 as a functional retromer subunit and showing that SNX6 depletion destabilizes SNX1 protein levels.

    Evidence RNAi loss-of-function screen with CI-MPR redistribution readout; co-immunoprecipitation of SNX6–SNX1

    PMID:17148574

    Open questions at the time
    • Motor coupling mechanism for retromer-associated tubule transport unknown
    • Relative contributions of SNX5 versus SNX6 not resolved
  3. 2009 High

    Two independent studies revealed that SNX6 directly binds p150(Glued) of dynein/dynactin, linking the ESCPE-1/retromer membrane tubule to microtubule-based transport and explaining how endosomal tubulovesicular carriers detach and traffic toward the TGN.

    Evidence Reciprocal co-immunoprecipitation, dominant-negative disruption, live cell imaging, C. elegans genetic epistasis

    PMID:19619496 PMID:19935774

    Open questions at the time
    • Structural basis of the SNX6–p150(Glued) interface unresolved
    • Whether SNX5 and SNX6 have distinct or redundant dynactin-binding roles unclear
  4. 2015 High

    The discovery that Chlamydia trachomatis IncE hijacks SNX5/SNX6 to the bacterial inclusion membrane demonstrated a host-defense role for the SNX6-containing retromer, as its depletion enhanced bacterial replication.

    Evidence AP-MS, co-immunoprecipitation, RNAi knockdown with bacterial progeny quantification

    PMID:26118995

    Open questions at the time
    • Whether pathogen subversion reflects a broader innate immune role for SNX6/retromer is untested
    • Structural basis of IncE–SNX6 interaction not determined in this study
  5. 2017 High

    CNS-specific Snx6 knockout revealed a retromer-independent neuronal function: SNX6 interacts with Homer1b/c to regulate its dendritic distribution and is required for normal dendritic spine density, surface AMPAR levels, synaptic transmission, and spatial memory.

    Evidence Conditional knockout mice with electrophysiology, Morris water maze, co-immunoprecipitation, confocal imaging

    PMID:28134614

    Open questions at the time
    • Mechanism by which SNX6 regulates Homer1b/c trafficking independently of retromer not defined
    • Whether AMPAR reduction is a direct or indirect consequence of Homer1b/c mislocalization unclear
  6. 2025 High

    SNX6 was shown to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to GluA1 assembly, resolving the molecular basis for AMPAR reduction: without SNX6, GluA2 is diverted to lysosomes, impairing constitutive and activity-dependent surface AMPAR expression, LTP, and memory.

    Evidence Conditional knockout mice, pulse-chase trafficking assays in hippocampal neurons, electrophysiology, behavioral tests

    PMID:41429886

    Open questions at the time
    • Cargo recognition mechanism by which SNX6 selects GluA2 for post-Golgi sorting is undefined
    • Whether SNX6 cooperates with other sorting factors at the TGN for GluA2 export is unknown
    • Relevance to neurodegenerative or neurodevelopmental disease in humans not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the full SNX1/SNX6 or SNX2/SNX6 heterodimer on membranes, the structural basis of the SNX6–p150(Glued) and SNX6–GluA2 interactions, and the mechanism by which VARP bridges ESCPE-1 to SNX27–Retromer remain to be established.
  • No high-resolution structure of the full SNX6-containing ESCPE-1 complex
  • Cargo recognition motifs on GluA2 for SNX6-mediated TGN export unidentified
  • In vivo reconstitution of the SNX27–ESCPE-1–Retromer supercomplex awaits peer-reviewed validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005768 endosome 4 GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 3 R-HSA-112316 Neuronal System 2
Partners
DCTN1GRIA2HOMER1RAB32SNX1SNX2SNX5VPS35
Complex memberships
ESCPE-1 (SNX1/SNX6 or SNX2/SNX6 heterodimer)Retromer-associated complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SNX6 was identified as a novel sorting nexin that interacts with members of the TGF-β family of receptor serine-threonine kinases (ActRIIB, TβRII, inactivated TβRI), as well as receptor tyrosine kinases, and forms strong heteromeric complexes with SNX1, SNX2, and SNX4, suggesting formation of oligomeric SNX complexes in vivo. Yeast two-hybrid screen and co-immunoprecipitation The Journal of biological chemistry Medium 11279102
2001 SNX6, along with SNX1, SNX2, SNX4, and SNX5, localizes to early endosomes (overlapping with EEA1) in HeLa cells, consistent with a role in endosomal sorting. Confocal microscopy with GFP-fusion proteins and endosome marker colocalization The Biochemical journal Medium 11485546
2006 RNAi knockdown screen identified SNX5 and SNX6 as required for retromer-mediated endosome-to-TGN retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); SNX6 co-immunoprecipitates with SNX1, forming a stable endosomally associated complex. Suppression of SNX5 and/or SNX6 caused significant post-translational loss of SNX1 protein levels. RNAi loss-of-function screen, immunoprecipitation, colocalization with SNX1 on early endosomes Journal of cell science High 17148574
2009 SNX6 interacts directly with the p150(Glued) subunit of the dynein/dynactin motor complex, and this interaction is required for recruitment of the motor complex to the membrane-associated retromer, formation and detachment of tubulovesicular sorting structures from endosomes, and CI-MPR retrieval from endosomes to the TGN. Disruption of the SNX6–p150(Glued) interaction blocks retrograde transport. Co-immunoprecipitation, dominant-negative disruption experiments, CI-MPR trafficking assay Cell research High 19935774
2009 Four distinct mammalian retromer complexes exist whose membrane-bound subcomplexes contain specific combinations of SNX1, SNX2, SNX5, and SNX6; SNX5/SNX6 associate with p150(Glued) of dynactin to regulate the spatial organization of the endosomal network and dynein-mediated transport, validated by genetic studies in C. elegans. Biochemical fractionation, Co-IP, C. elegans genetic epistasis, live cell imaging Developmental cell High 19619496
2011 The N-terminal region of BRMS1 (residues 51–98), which mediates interaction with SNX6, forms an antiparallel coiled-coil that homo-oligomerizes into a hexameric (trimer of dimers) conformation, as determined by X-ray crystallography and hydrodynamic experiments. X-ray crystallography, analytical ultracentrifugation/hydrodynamic analysis Journal of molecular biology Medium 21777593
2015 The Chlamydia trachomatis inclusion membrane protein IncE binds directly to SNX5/6 (retromer components), relocalizing them to the inclusion membrane and augmenting inclusion membrane tubulation; depletion of retromer components (including SNX6) enhances bacterial progeny production, demonstrating that the SNX5/6-containing retromer restricts Chlamydia infection. AP-MS, co-immunoprecipitation, fluorescence microscopy, RNAi knockdown with bacterial progeny assay Cell host & microbe High 26118995
2016 miR-98-5p negatively regulates SNX6 expression by targeting its 3′-UTR; downregulation of miR-98-5p upregulates SNX6 and decreases SNX6-dependent levels of Aβ40, Aβ42, BACE1, sAPPβ, and βCTF in neuronal cells, indicating SNX6 participates in amyloid precursor protein processing. 3′-UTR luciferase reporter assay, miRNA overexpression/inhibition, Western blot for APP processing products Journal of molecular neuroscience Medium 27541017
2017 CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory and loss of dendritic spines from distal dendrites of hippocampal CA1 pyramidal neurons. SNX6 interacts with the postsynaptic scaffold Homer1b/c and regulates its distribution in the dendritic shaft independently of retromer function. Loss of SNX6 reduces surface AMPAR levels and impairs AMPAR-mediated synaptic transmission. Conditional knockout mice, electrophysiology, co-immunoprecipitation, confocal imaging, behavioral tests (Morris water maze) eLife High 28134614
2018 SNX1 and SNX6 form a 1:1 heterodimer in solution (from both worm and human proteins), requiring co-expression of both subunits and glycerol in buffer for stability; this biochemical reconstitution provides the basis for structural and in vitro transport studies of the ESCPE-1 complex. Recombinant co-expression and purification, size-exclusion chromatography, solution biochemistry Protein expression and purification Medium 29908913
2019 Rab32 directly interacts with SNX6, and both Rab32 and SNX6 affect the localization of CI-MPR (recycled by retromer to the TGN), linking Rab32 to SNX6/retromer-dependent Golgi trafficking. Co-immunoprecipitation, fluorescence microscopy, CI-MPR localization assay PloS one Medium 30640902
2024 ESCPE-1 (SNX2/SNX6 heterodimer) deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted system using purified mammalian proteins, but does not recruit Retromer on its own; VARP is required to reconstitute the proposed endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes. In vitro membrane tubulation reconstitution with purified proteins, AlphaFold2 Multimer modeling, biochemical binding assays bioRxivpreprint Medium bio_10.1101_2024.07.11.603126
2025 SNX6 selectively mediates sorting of newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to assembly with GluA1; loss of SNX6 diverts GluA2 to lysosomal degradation, reducing constitutive and activity-dependent surface AMPAR expression, impairing AMPAR-mediated synaptic transmission, NMDAR-dependent LTP, and causing learning and memory deficits. Conditional knockout mice, hippocampal neuron cultures, pulse-chase trafficking assays, electrophysiology, Western blot, confocal imaging Communications biology High 41429886

Source papers

Stage 0 corpus · 39 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
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
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
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2009 The retromer coat complex coordinates endosomal sorting and dynein-mediated transport, with carrier recognition by the trans-Golgi network. Developmental cell 250 19619496
2006 A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer. Journal of cell science 212 17148574
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2018 LZTR1 is a regulator of RAS ubiquitination and signaling. Science (New York, N.Y.) 180 30442766
2015 Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. Cell host & microbe 167 26118995
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2005 Scanning the human proteome for calmodulin-binding proteins. Proceedings of the National Academy of Sciences of the United States of America 139 15840729
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2001 A large family of endosome-localized proteins related to sorting nexin 1. The Biochemical journal 131 11485546
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2001 Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases. The Journal of biological chemistry 111 11279102
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2009 The retromer component SNX6 interacts with dynactin p150(Glued) and mediates endosome-to-TGN transport. Cell research 101 19935774
2018 TIM-1 Ubiquitination Mediates Dengue Virus Entry. Cell reports 94 29742433
2016 miR-98-5p Acts as a Target for Alzheimer's Disease by Regulating Aβ Production Through Modulating SNX6 Expression. Journal of molecular neuroscience : MN 46 27541017
2017 Ablation of SNX6 leads to defects in synaptic function of CA1 pyramidal neurons and spatial memory. eLife 22 28134614
2019 Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking. PloS one 20 30640902
2011 The structure of BRMS1 nuclear export signal and SNX6 interacting region reveals a hexamer formed by antiparallel coiled coils. Journal of molecular biology 11 21777593
2019 Pb exposure reduces the expression of SNX6 and Homer1 in offspring rats and PC12 cells. Toxicology 7 30738087
2018 Expression and purification of the SNX1/SNX6 complex. Protein expression and purification 7 29908913
2025 SNX6-mediated subunit-specific secretory trafficking of AMPA receptors regulates synaptic function and plasticity. Communications biology 0 41429886