Affinage

SNX8

Sorting nexin-8 · UniProt Q9Y5X2

Length
465 aa
Mass
52.6 kDa
Annotated
2026-06-10
15 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX8 (yeast Mvp1) is a PX-BAR sorting nexin that drives a retromer-independent endosomal membrane-remodeling and recycling pathway conserved from yeast to humans (PMID:34524084). In its resting state the full-length protein adopts an autoinhibited tetramer (dimer-of-dimers) in which the membrane-engaging BAR surfaces and PX lipid-binding sites are occluded; the N-terminal low-complexity region mediates tetramerization, and its removal yields an active dimer with enhanced membrane association and remodeling (PMID:32198400). Once active, SNX8/Mvp1 deforms the endosomal membrane, captures cargo bearing defined sorting motifs into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze scission and tubule release (PMID:7862158, PMID:34524084); it can also cooperate with retromer via association with the Vps26 subunit to recycle tyrosine-motif cargo such as Vps68 (PMID:41883240). The same tubulating activity supports lysosome reformation, where loss of SNX8 produces enlarged lysosomes and storage defects modeling Lysosomal Storage Disorders that are rescued by SNX8 restoration or small molecules enhancing SNX8-lysosome binding (PMID:38519472), and it promotes non-amyloidogenic APP trafficking through the endosomal pathway, reducing Aβ accumulation (PMID:31551717). In mammals SNX8 additionally serves as a signaling scaffold in antiviral and inflammatory responses: it recruits the PI3-kinase VPS34 to the adaptor MITA/STING to enable ER-to-perinuclear trafficking and activation after DNA virus infection (PMID:30321235), translocates to mitochondria to promote VISA/MAVS aggregation during RNA virus infection (PMID:31511639), and bridges JAK1 and IKKβ as a phosphorylation-dependent scaffold in the noncanonical IFNγ pathway (PMID:29180417).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1995 Medium

    Established the first functional link for the SNX8 ortholog, showing Mvp1 acts together with a dynamin-like GTPase to drive traffic to the vacuole, framing it as a membrane-trafficking factor.

    Evidence Multicopy suppressor genetic screen, epistasis, and colocalization with Vps1p in yeast

    PMID:7862158

    Open questions at the time
    • Did not define direct membrane-binding or scission mechanism
    • No structural basis for Mvp1-Vps1 cooperation
  2. 2017 High

    Revealed a non-trafficking scaffold role, showing SNX8 bridges JAK1 and IKKβ and must itself be tyrosine-phosphorylated to organize the noncanonical IFNγ signaling complex against intracellular bacteria.

    Evidence Reciprocal Co-IP, phosphosite mutagenesis (Tyr95/Tyr126), and Snx8-/- Listeria infection model

    PMID:29180417

    Open questions at the time
    • Structural basis of JAK1/IKKβ scaffolding unknown
    • Relationship to its endosomal PX-BAR function unresolved
  3. 2018 High

    Showed SNX8 functions as an antiviral adaptor by recruiting VPS34 to STING to license its ER-to-perinuclear trafficking, connecting SNX8's trafficking biology to innate immune adaptor activation.

    Evidence Co-IP of VPS34-SNX8-MITA complex, trafficking assays, and Snx8-/- HSV-1 infection model

    PMID:30321235

    Open questions at the time
    • Whether PX/BAR membrane-deforming activity is required for STING trafficking not dissected
    • Direct binding interfaces not mapped
  4. 2019 High

    Extended SNX8's antiviral scaffolding to RNA virus sensing, showing it relocates to mitochondria and promotes aggregation of the adaptor VISA/MAVS to enable downstream signaling.

    Evidence Translocation/fractionation assay, Co-IP, VISA aggregation assay, and Snx8-/- RNA virus infection model

    PMID:31511639

    Open questions at the time
    • Trigger for cytosol-to-mitochondria translocation unknown
    • Mechanism by which SNX8 nucleates VISA aggregation undefined
  5. 2019 Medium

    Linked SNX8 to disease-relevant endosomal cargo handling by showing it promotes non-amyloidogenic APP processing and limits Aβ accumulation.

    Evidence Endosomal localization, overexpression/knockdown with APP cleavage and Aβ ELISA, and APP/PS1 mouse behavioral rescue

    PMID:31551717

    Open questions at the time
    • Direct SNX8-APP interaction not demonstrated
    • Sorting motif on APP recognized by SNX8 not identified
  6. 2020 High

    Defined the regulatory switch for SNX8 membrane engagement, showing full-length Mvp1 is an autoinhibited tetramer whose PX and BAR surfaces must be unmasked for activity.

    Evidence Cryo-EM of full-length Mvp1 with deletion mutagenesis and membrane-binding/remodeling assays

    PMID:32198400

    Open questions at the time
    • Physiological signal that relieves autoinhibition unknown
    • Whether mammalian SNX8 uses identical autoinhibition not directly shown
  7. 2021 High

    Resolved the core endosomal mechanism, showing SNX8/Mvp1 deforms membranes, sorts motif-bearing cargo into tubules, and recruits Vps1 for scission in a retromer-independent recycling pathway conserved to human SNX8.

    Evidence Live-cell imaging, cargo-sorting and tubule assays, reconstitution in yeast, and human SNX8 complementation

    PMID:34524084

    Open questions at the time
    • Full cargo repertoire incompletely defined
    • Coordination between Vps1 recruitment and autoinhibition release unresolved
  8. 2024 High

    Connected SNX8 tubulation to organelle homeostasis and human disease, showing it drives lysosome reformation and that restoring its activity reverses lysosomal storage phenotypes.

    Evidence SNX8 KO lysosome morphology/storage assays, overexpression and AAV rescue in LSD mouse model, and small-molecule SNX8-lysosome binding screen

    PMID:38519472

    Open questions at the time
    • Cargo and scission machinery for lysosomal tubulation not specified
    • Mechanism of small-molecule enhancement of SNX8 binding undefined
  9. 2026 Medium

    Showed SNX8 is not strictly retromer-independent, demonstrating cooperation with retromer (Vps26) for recycling of tyrosine-motif cargo Vps68.

    Evidence Genetic deletion, vacuolar degradation assays, sorting-signal mutagenesis, and Mvp1-Vps26 co-IP in yeast

    PMID:41883240

    Open questions at the time
    • Single co-IP without reciprocal/structural validation of the Mvp1-Vps26 interface
    • Generality of retromer cooperation beyond Vps68 unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single PX-BAR protein partitions between autoinhibited membrane remodeling and its distinct cytosolic/mitochondrial signaling-scaffold roles, and what signals dictate each, remains unresolved.
  • No unified model linking autoinhibition release to immune-scaffold activation
  • Structural basis of mammalian signaling complexes (STING/VPS34, VISA, JAK1/IKKβ) not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 2 GO:0005739 mitochondrion 1 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 1
Partners
IKKBJAK1STING/MITAVISA/MAVSVPS1VPS26VPS34
Complex memberships
retromer (via Vps26 association)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Yeast Mvp1p (SNX8 ortholog) genetically interacts with the dynamin-like GTPase Vps1p and is required for vacuolar protein sorting; overproduction of Mvp1p suppresses dominant-negative vps1 alleles in a manner dependent on wild-type Vps1p, and Mvp1p colocalizes with Vps1p in vps1Δ and vps27Δ cells, indicating they act in concert to promote membrane traffic to the vacuole. Multicopy suppressor genetic screen, epistasis analysis, fluorescence colocalization in yeast Molecular and cellular biology Medium 7862158
2020 Full-length Mvp1 (yeast SNX8 ortholog) forms an autoinhibited tetramer (dimer-of-dimers) in which the membrane-interacting BAR surfaces are sequestered and PX lipid-binding sites are occluded; the N-terminal low-complexity region is essential for tetramerization, and deletion of this region produces a dimer with enhanced membrane association and remodeling activity, revealing an autoinhibitory mechanism for membrane binding. Cryo-EM structure of full-length Mvp1, deletion mutagenesis, membrane-binding/remodeling assays Nature communications High 32198400
2021 Mvp1/SNX8 deforms the endosomal membrane, sorts cargos containing a specific sorting motif into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and tubule release, defining a retromer-independent endosomal recycling pathway conserved from yeast to humans; human SNX8 likewise mediates formation of endosomal recycling tubules. Live-cell fluorescence microscopy, cargo-sorting assays, genetic and biochemical reconstitution in yeast, human SNX8 functional complementation eLife High 34524084
2026 Recycling of the endosomal protein Vps68 in yeast depends on both retromer and Mvp1/SNX8; a tyrosine-based recycling signal in the cytosolic tail of Vps68 is required for Mvp1-dependent recycling, and co-immunoprecipitation detected a physical association between Mvp1 and the retromer subunit Vps26, indicating Mvp1 can cooperate with retromer. Genetic deletion analysis, vacuolar degradation assays, identification of tyrosine recycling signal by mutagenesis, co-immunoprecipitation Biology open Medium 41883240
2017 SNX8 interacts with JAK1 and IKKβ, promotes their association, and acts as a scaffold in the IFNγ-triggered noncanonical signaling pathway; IFNγ induces JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promotes IKKβ recruitment to the JAK1 complex and is required for IKKβ oligomerization and autophosphorylation at Ser177, selectively inducing downstream effector genes important for defense against Listeria monocytogenes. Co-immunoprecipitation, phosphorylation-site mutagenesis, Snx8-/- mouse infection model, downstream gene induction assays Proceedings of the National Academy of Sciences of the United States of America High 29180417
2018 SNX8 recruits the class III phosphatidylinositol 3-kinase VPS34 to the innate immune adaptor MITA/STING, and this recruitment is required for trafficking of MITA from the ER to perinuclear microsomes after DNA virus infection, which is critical for MITA activation and induction of antiviral genes; Snx8-/- mice show impaired antiviral cytokine responses and higher HSV-1 lethality. Co-immunoprecipitation, Snx8-/- mouse infection model, subcellular trafficking assays, downstream gene induction assays PLoS pathogens High 30321235
2019 Upon RNA virus infection SNX8 translocates from the cytosol to mitochondria, increases its association with the mitochondrial antiviral signaling adaptor VISA/MAVS, and promotes VISA aggregation, which is required for recruitment of downstream signaling components and induction of antiviral genes; Snx8-/- mice show impaired RNA virus-triggered cytokine responses and higher lethality. Subcellular fractionation/translocation assay, co-immunoprecipitation, VISA aggregation assay, Snx8-/- mouse infection model Cellular & molecular immunology High 31511639
2019 SNX8 localizes predominantly to early and late endosomes; SNX8 overexpression enhances total APP levels, cell-surface APP distribution, and non-amyloidogenic soluble APPα cleavage, while SNX8 depletion elevates Aβ levels; overexpression of SNX8 reduces Aβ accumulation and rescues cognitive impairment in APP/PS1 AD mice, implicating SNX8 in non-amyloidogenic APP trafficking through the endosomal pathway. Subcellular localization by fluorescence microscopy, SNX8 overexpression and siRNA knockdown in cells, APP cleavage and Aβ ELISA, APP/PS1 mouse behavioral rescue Frontiers in cellular neuroscience Medium 31551717
2024 SNX8 promotes lysosome tubulation required for lysosome reformation; loss of SNX8 causes enlarged lysosomes and defective lysosomal storage characteristic of Lysosomal Storage Disorders (LSDs), while SNX8 overexpression or AAV-mediated SNX8 delivery to the brain rescues LSD phenotypes in human cells and mice; small molecules that enhance SNX8-lysosome binding similarly reverse LSD phenotypes. SNX8 KO in human cells (lysosome morphology and storage assays), SNX8 overexpression rescue, AAV delivery in LSD mouse model, small-molecule screen with SNX8-lysosome binding assay Nature communications High 38519472
2013 SNX8 is expressed in neurons (soma) but not astrocytes or microglia; overexpression of GFP-SNX8 under moderately high cholesterol conditions caused redistribution of cholesterol within neurons, creating a phenotype similar to lysosomal cholesterol accumulation, suggesting SNX8 modulates intraneuronal cholesterol trafficking. Immunofluorescence localization in primary CNS cells, GFP-SNX8 lentiviral overexpression, filipin cholesterol staining Journal of molecular neuroscience Low 24362679

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The Saccharomyces cerevisiae MVP1 gene interacts with VPS1 and is required for vacuolar protein sorting. Molecular and cellular biology 70 7862158
2018 SNX8 modulates innate immune response to DNA virus by mediating trafficking and activation of MITA. PLoS pathogens 39 30321235
2021 A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling. eLife 31 34524084
2019 SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA. Cellular & molecular immunology 26 31511639
2017 SNX8 mediates IFNγ-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes. Proceedings of the National Academy of Sciences of the United States of America 26 29180417
2020 The cryo-EM structure of the SNX-BAR Mvp1 tetramer. Nature communications 21 32198400
2014 Trafficking of the myrosinase-associated protein GLL23 requires NUC/MVP1/GOLD36/ERMO3 and the p24 protein CYB. The Plant journal : for cell and molecular biology 16 24330158
2013 The expression of neuronal sorting nexin 8 (SNX8) exacerbates abnormal cholesterol levels. Journal of molecular neuroscience : MN 15 24362679
2019 Small 7p22.3 microdeletion: Case report of Snx8 haploinsufficiency and neurological findings. European journal of medical genetics 11 31568860
2024 SNX8 enables lysosome reformation and reverses lysosomal storage disorder. Nature communications 10 38519472
2019 SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse. Frontiers in cellular neuroscience 10 31551717
2004 Cloning, sequencing and functional analysis of Magnaporthe grisea MVP1 gene, a hex-1 homolog encoding a putative 'woronin body' protein. FEMS microbiology letters 10 14734169
2021 Cloning and functional analysis of SNX8 from grass carp (Ctenopharyngodon idellus). Fish & shellfish immunology 2 34920130
2026 Recycling of Vps68 depends on retromer and Mvp1/SNX8. Biology open 0 41883240
2025 Cryptosporidium MVP1, modulates intestinal microvilli by interacting with host EBP50 and CDC42. Trends in parasitology 0 40527704

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