Affinage

ZFYVE26

Zinc finger FYVE domain-containing protein 26 · UniProt Q68DK2

Length
2539 aa
Mass
284.6 kDa
Annotated
2026-06-11
26 papers in source corpus 11 papers cited in narrative 11 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

ZFYVE26/spastizin is a FYVE-domain protein that, together with spatacsin (SPG11) and the AP-5 adaptor complex, forms a coat-like assembly governing endolysosomal membrane trafficking and autophagic lysosome reformation (PMID:23825025). The three proteins coimmunoprecipitate at ~1:1:1:1:1:1 stoichiometry and colocalize on a late endosomal/lysosomal compartment, where SPG15 docks the coat onto membranes through PI3P binding by its FYVE domain while SPG11 forms the scaffold (PMID:23825025); cryo-EM resolves the SPG11-SPG15 heterodimer as a head-to-head W-shaped complex that, with AP-5 in a super-open conformation, binds PI3P, senses membrane curvature, and drives membrane remodeling including autolysosome tubulation in vitro (PMID:40175557). Membrane recruitment depends on coincidence detection of PI3P and Rag GTPases, with GDP-locked RagC promoting and GTP-locked RagA preventing recruitment, linking the complex to the mTORC1 pathway and autophagic lysosome reformation (PMID:33464297). Loss of spastizin blocks autophagosome maturation and autophagosome-endosome fusion—the latter via its interactions with RAB5A and RAB11, with constitutively active RAB5A partially rescuing the defect—producing accumulation of immature autophagosomes, enlarged LAMP1-positive lysosomes, and depletion of free lysosomes (PMID:24284334, PMID:30081747, PMID:24367272). Spastizin and spatacsin mutually stabilize one another (PMID:24999486). In neurons, deficiency causes defective anterograde axonal transport, lipid accumulation, mitochondrial fragmentation with reduced ATP production, and synaptic vulnerability to excitotoxicity (PMID:35313342, PMID:41192643), establishing ZFYVE26 as a determinant of neuronal lysosomal and mitochondrial homeostasis.

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Low

    Established the first cellular context for an uncharacterized FYVE-domain protein by placing it at ER/endosomal compartments, implicating it in intracellular trafficking.

    Evidence Immunofluorescence colocalization with organelle markers in cultured cells

    PMID:18394578

    Open questions at the time
    • Single colocalization experiment with no functional follow-up
    • No interaction partners or molecular activity defined
    • Did not distinguish ER from endosomal residence functionally
  2. 2013 High

    Defined spastizin as a stoichiometric subunit of an AP-5/SPG11/SPG15 coat complex on late endosomes/lysosomes, assigning it a membrane-docking role via PI3P binding and establishing a shared trafficking phenotype with AP-5.

    Evidence Reciprocal Co-IP with stoichiometry, RNAi epistasis with mannose 6-phosphate receptor trapping, colocalization, and in vitro SPG11-AP-5 binding

    PMID:23825025

    Open questions at the time
    • FYVE-PI3P docking proposed but not directly demonstrated in this study
    • Mechanism of cargo handling by the coat unresolved
    • No in vivo validation
  3. 2013 High

    Confirmed the endolysosomal trafficking role in vivo, showing genetic loss produces intraneuronal LAMP1-positive deposits and lysosomal dysregulation.

    Evidence Zfyve26 knockout mouse with fractionation, EM, EEA1/Lamp1 immunostaining, and lysosomal enzyme assays

    PMID:24367272

    Open questions at the time
    • Did not resolve the molecular step disrupted
    • Link to autophagy not yet established here
    • Mechanism connecting deposits to neurodegeneration unknown
  4. 2013 Medium

    Identified spastizin as a determinant of autophagosome maturation, extending its role from endosomal trafficking to autophagy.

    Evidence Patient fibroblasts/lymphoblasts and primary neurons with LC3B-II and p62 western blots and autophagosome quantification

    PMID:24284334

    Open questions at the time
    • Did not define which fusion or maturation step is blocked
    • No structural or interaction mechanism
    • Single lab
  5. 2014 Medium

    Showed spastizin and spatacsin are interdependently stabilized and that patient cells exhibit lysosomal enlargement and storage, reinforcing an obligate heterodimer with a lysosomal phenotype.

    Evidence Patient-derived fibroblasts with LAMP1 immunofluorescence, EM, and western blot stability analysis

    PMID:24999486

    Open questions at the time
    • Mechanism of mutual stabilization not structurally defined
    • Lysosomal storage cargo not identified
  6. 2018 High

    Distinguished spastizin's specific function from spatacsin by showing only ZFYVE26 controls RAB5A/RAB11 activation and autophagosome-endosome fusion, with RAB5A rescue pinpointing the defective step.

    Evidence Co-IP for RAB5A/RAB11, autophagosome-endosome fusion assay, constitutively active RAB5A rescue, and autophagic lysosome reformation assay in patient cells

    PMID:30081747

    Open questions at the time
    • How spastizin regulates RAB activation mechanistically unresolved
    • Direct vs indirect RAB interaction not separated
    • Relationship between fusion defect and ALR defect not fully ordered
  7. 2021 High

    Resolved how the coat is recruited to membranes, showing PI3P–Rag GTPase coincidence detection and linking complex localization to mTORC1-coupled autophagic lysosome reformation.

    Evidence Live-cell imaging with dominant Rag GTPase mutants, FYVE-domain PI3P binding assays, and starvation-dependent recruitment

    PMID:33464297

    Open questions at the time
    • Direct physical Rag-complex contact not structurally mapped
    • How GDP-RagC vs GTP-RagA states are sensed unresolved
  8. 2022 Medium

    Mapped the neuronal consequences of spastizin loss, connecting lysosomal/autophagy dysfunction to axonal transport, lipid handling, and synaptic vulnerability.

    Evidence Patient fibroblasts and KO mouse cortical neurons with axonal transport imaging, autophagic flux, lipid staining, electrophysiology, and excitotoxicity assays

    PMID:35313342

    Open questions at the time
    • Causal chain from lysosomal defect to transport failure not established
    • Single lab
    • Lipid species not identified
  9. 2023 Medium

    Validated lysosomes as a tractable therapeutic node by showing calcium/calpain- and lysosome-modulating compounds rescue ALR defects across patient cells and a Drosophila model.

    Evidence Compound library screen in patient cells, Drosophila SPG15 loss-of-function model with lysosome quantification and locomotor readouts

    PMID:36029068

    Open questions at the time
    • Molecular targets of rescue compounds not all defined
    • Whether rescue restores neuronal function long-term unknown
  10. 2025 High

    Provided the structural mechanism, showing the W-shaped SPG11-SPG15 heterodimer with super-open AP-5 binds PI3P, senses curvature, and remodels membranes to initiate autolysosome tubulation.

    Evidence Cryo-EM structure, in vitro membrane remodeling and PI3P binding reconstitution, and domain mutagenesis validating SPG11 N-terminal AP-5 contact

    PMID:40175557

    Open questions at the time
    • In-cell relevance of curvature sensing not directly tested
    • Conformational coupling to Rag/PI3P recruitment not resolved structurally
  11. 2025 Medium

    Extended spastizin function beyond endolysosomal trafficking by linking it to mitochondrial integrity, with DRP1 inhibition rescuing fragmentation and downstream neuronal pathology.

    Evidence Patient iPSC-derived cortical neurons with ATP, mitochondrial morphology, oxidative stress and apoptosis assays plus DRP1 inhibitor P110 rescue

    PMID:41192643

    Open questions at the time
    • Whether mitochondrial defect is primary or secondary to lysosomal dysfunction unresolved
    • Mechanism of spastizin mitochondrial localization unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally defined coat coordinates PI3P/Rag coincidence detection, RAB-dependent fusion, and membrane remodeling into a single ordered ALR cycle in neurons remains unresolved.
  • No integrated model linking recruitment, fusion, and tubulation in time
  • Causal hierarchy among lysosomal, transport, and mitochondrial defects unestablished
  • No structure of the membrane-bound holocomplex with Rag GTPases

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-5653656 Vesicle-mediated transport 3
Partners
AP5Z1RAB11RAB5ARAGARAGCSPG11
Complex memberships
AP-5/SPG11/SPG15 coat complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 ZFYVE26 (spastizin) encodes a zinc-finger FYVE domain-containing protein that partially colocalizes with markers of endoplasmic reticulum and endosomes in cultured cells, suggesting a role in intracellular trafficking. Subcellular localization by immunofluorescence colocalization with organelle markers in cultured cells American journal of human genetics Low 18394578
2013 AP-5 complex subunits coimmunoprecipitate with SPG15 (spastizin) and SPG11 (spatacsin) at ~1:1:1:1:1:1 stoichiometry from both cytosol and detergent-extracted membranes. Knockdown of SPG15 phenocopies AP-5 subunit knockdowns, causing cation-independent mannose 6-phosphate receptor trapping in early endosome clusters. AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment. The N-terminal β-propeller-like domain of SPG11 interacts in vitro with AP-5. SPG15 is proposed to dock the coat onto membranes via PI3P binding through its FYVE domain, and SPG11 forms a scaffold. Co-immunoprecipitation from cytosol and membranes; RNAi knockdown with endosomal trafficking phenotype readout; colocalization by immunofluorescence; in vitro binding assay (SPG11 domain vs AP-5) Molecular biology of the cell High 23825025
2013 In Zfyve26 knockout mice, ZFYVE26 associates with intracellular vesicles positive for early endosomal marker EEA1 and co-fractionates with a component of the AP-5 complex. Loss of Zfyve26 causes accumulation of large intraneuronal Lamp1-positive membrane deposits, increased density of Lamp1-positive compartments on density gradients, and elevated lysosomal enzyme levels, supporting a role in endolysosomal membrane trafficking. Zfyve26 knockout mouse model; subcellular fractionation/density gradient; immunofluorescence with EEA1 and Lamp1 markers; electron microscopy; enzymatic activity assay for lysosomal enzymes PLoS genetics High 24367272
2014 SPG15 patient-derived fibroblasts show selective enlargement of LAMP1-positive structures and abnormal lysosomal storage by electron microscopy. The stabilities of spastizin (ZFYVE26) and spatacsin (SPG11) are interdependent, indicating mutual stabilization of the two proteins. Patient-derived fibroblast analysis; immunofluorescence for LAMP1; electron microscopy; western blot for protein stability Annals of clinical and translational neurology Medium 24999486
2013 Patient-derived fibroblasts and lymphoblasts carrying ZFYVE26 mutations show accumulation of immature autophagosomes and increased MAP1LC3B-II and SQSTM1/p62 levels, establishing ZFYVE26 as a key determinant of autophagosome maturation. This defect was replicated in primary neurons. Patient-derived fibroblast/lymphoblast analysis; western blot for LC3B-II and p62; autophagosome quantification; replication in primary neurons Autophagy Medium 24284334
2018 ZFYVE26 and SPG11 both interact with RAB5A and RAB11 (regulators of endosome trafficking and maturation), but only ZFYVE26 mutations affect RAB protein interactions and activation. ZFYVE26 mutations impair fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step. Expression of constitutively active RAB5A partially rescues the autophagy defect caused by ZFYVE26 mutations. ZFYVE26 and SPG11 are both required for autophagic lysosome reformation. Co-immunoprecipitation for RAB5A/RAB11 interactions; patient-derived cells with autophagosome-endosome fusion assay; rescue experiment with constitutively active RAB5A; autophagic lysosome reformation assay Autophagy High 30081747
2021 Recruitment of the AP-5/SPG11/SPG15 complex to late endosomes/lysosomes occurs by coincidence detection requiring both PI3P and Rag GTPases. The SPG15 FYVE domain alone localizes to early endosomes but PI3P binding cooperates with Rag GTPases for complex recruitment to late endosomes/lysosomes. GDP-locked RagC promotes recruitment, while GTP-locked RagA prevents it, linking the complex to the mTORC1 pathway and autophagic lysosome reformation. Live-cell imaging and subcellular localization assays; dominant-active/dominant-negative Rag GTPase constructs; PI3P binding assays via FYVE domain; starvation conditions The Journal of cell biology High 33464297
2022 Loss of SPG15 protein in patient fibroblasts and SPG15 KO primary cortical neurons causes defective anterograde transport, impaired neurite outgrowth, axonal swelling, reduced autophagic flux, lipid accumulation within the lysosomal compartment, and synaptic dysfunction with augmented vulnerability to glutamate-induced excitotoxicity. Patient fibroblasts and SPG15 KO mouse primary cortical neurons; live imaging of axonal transport; neurite outgrowth assays; autophagic flux assays; lipid staining; electrophysiology for synaptic function; glutamate excitotoxicity assay Human molecular genetics Medium 35313342
2023 SPG15-related ZFYVE26 mutations cause autophagic lysosome reformation defects with lysosome enlargement, free lysosome depletion, and autophagosome accumulation. Pharmacological rescue with compounds modulating intracellular calcium, the calcium-calpain pathway, or lysosomal function (including SMER28, verapamil, Bay K8644, 2',5'-dideoxyadenosine, trehalose, trifluoperazine) improves lysosome biogenesis and function in a Drosophila SPG15 loss-of-function model and in patient-derived cells, validating lysosomes as a key pharmacological target. Patient-derived cell compound library screen; SPG15 loss-of-function Drosophila model; autophagosome and lysosome quantification; locomotor deficit readout in Drosophila Brain : a journal of neurology Medium 36029068
2025 Cryo-EM structure of SPG11-SPG15 reveals a W-shaped complex intertwined in a head-to-head fashion. The N-terminal region of SPG11 is required for AP-5 complex interaction and assembly. The AP-5 complex adopts a super-open conformation. The AP5-SPG11-SPG15 complex binds PI3P molecules, senses membrane curvature, and drives membrane remodeling in vitro, including initiation of autolysosome tubulation. Cryo-electron microscopy; in silico structural predictions; in vitro membrane remodeling assay; PI3P binding assay; domain deletion/mutagenesis for AP5 interaction Nature structural & molecular biology High 40175557
2025 Spastizin partially localizes to mitochondria in SPG15 patient iPSC-derived cortical neurons. SPG15 neurons exhibit reduced ATP production and increased mitochondrial fragmentation. Inhibition of mitochondrial fission protein DRP1 with peptide P110 restores mitochondrial morphology, reduces oxidative stress, and suppresses axonal swellings and apoptosis in SPG15 neurons. iPSC-derived cortical neurons from SPG15 patients; ATP production assay; mitochondrial morphology imaging; DRP1 inhibitor (P110) treatment; axonal swelling quantification; oxidative stress assay; apoptosis assay Neurobiology of disease Medium 41192643

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. American journal of human genetics 165 18394578
2014 Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain : a journal of neurology 132 24833714
2013 Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15. Molecular biology of the cell 98 23825025
2014 Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Annals of clinical and translational neurology 92 24999486
2013 A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system. PLoS genetics 79 24367272
2009 SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 77 19805727
2009 Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia. Journal of neurology, neurosurgery, and psychiatry 60 19917823
2019 "Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia. AJNR. American journal of neuroradiology 57 30606727
2001 SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 51 11342696
2008 Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity. Archives of neurology 49 18332254
2018 ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. Autophagy 47 30081747
2021 Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex. The Journal of cell biology 25 33464297
2013 ZFYVE26/SPASTIZIN: a close link between complicated hereditary spastic paraparesis and autophagy. Autophagy 17 24284334
2008 Spastic paraplegia with thinning of the corpus callosum and white matter abnormalities: further mutations and relative frequency in ZFYVE26/SPG15 in the Italian population. Journal of the neurological sciences 17 19084844
2007 Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families. Neurogenetics 17 17661097
2023 The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15. Brain : a journal of neurology 16 36315648
2022 SPG15 protein deficits are at the crossroads between lysosomal abnormalities, altered lipid metabolism and synaptic dysfunction. Human molecular genetics 14 35313342
2020 Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia. Journal of the neurological sciences 14 32006740
2023 Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia. Brain : a journal of neurology 13 36029068
2021 Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia. Journal of the Formosan Medical Association = Taiwan yi zhi 7 33637369
2019 A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene. The International journal of neuroscience 6 31385551
2025 Structural basis for membrane remodeling by the AP5-SPG11-SPG15 complex. Nature structural & molecular biology 5 40175557
2020 Topiramate-Responsive Tremor in a Novel Pathogenic Variant of SPG15 Patient. Clinical neuropharmacology 3 32501858
2018 Novel c.C2254T (p.Q752*) mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis. Journal of genetics 2 30555096
2023 Case report: Hereditary spastic paraplegia with a novel homozygous mutation in ZFYVE26. Frontiers in neurology 1 37681008
2025 Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction. Neurobiology of disease 0 41192643

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