id: Q68DK2 gene_symbol: ZFYVE26 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ZFYVE26 encodes spastizin/SPG15, a FYVE-domain PI3P-binding protein that functions with SPG11/spatacsin and AP-5 in endolysosomal membrane remodeling. The strongest protein-homeostasis evidence supports a core role in autophagic lysosome reformation, lysosomal membrane organization, membrane bending, and autophagosome maturation through PI3P-dependent recruitment to lysosomal/late-endosomal membranes. ZFYVE26 also has experimentally supported cytokinesis and HR-DSBR roles, but its principal cellular role is endolysosomal membrane remodeling. alternative_products: - name: '1' id: Q68DK2-1 - name: '2' id: Q68DK2-2 sequence_note: VSP_030339 - name: '4' id: Q68DK2-4 sequence_note: VSP_041049, VSP_041050 - name: '3' id: Q68DK2-3 sequence_note: VSP_030338, VSP_030340, VSP_030341 - name: '5' id: Q68DK2-5 sequence_note: VSP_058963, VSP_058964 existing_annotations: - term: id: GO:0005813 label: centrosome evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: &id001 summary: Centrosome localization is supported in the FYVE-CENT cytokinesis paper, but it reflects the non-core cytokinesis role rather than the endolysosomal proteostasis core. action: KEEP_AS_NON_CORE reason: Retain as non-core localization tied to the midbody/cytokinesis context. supported_by: - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0030496 label: midbody evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: &id002 summary: Midbody localization is directly supported and mechanistically linked to PI3P-dependent cytokinesis, but it is non-core for this proteostasis-focused review. action: KEEP_AS_NON_CORE reason: Retain as non-core localization tied to cytokinesis. supported_by: - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: &id003 summary: 'ZFYVE26/spastizin has an informative FYVE-domain molecular function: PI3P binding. This binding recruits spastizin to PI3P-positive membranes in cytokinesis and is also required for lysosomal targeting/AP5-SPG11-SPG15 membrane remodeling.' action: ACCEPT reason: Retain PI3P binding as the core molecular function that links spastizin to both midbody biology and the proteostasis-relevant endolysosomal membrane-remodeling machinery. supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: &id008 summary: ZFYVE26/FYVE-CENT has direct midbody/cytokinesis evidence, but this is not the core proteostasis function emphasized by the PN review. action: KEEP_AS_NON_CORE reason: Retain as a supported non-core cytokinesis role while prioritizing ALR/endolysosomal membrane organization as the proteostasis core. supported_by: - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0000281 label: mitotic cytokinesis evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Mitotic cytokinesis is supported by the FYVE-CENT midbody paper, but it is a non-core role relative to ZFYVE26/spastizin proteostasis biology. action: KEEP_AS_NON_CORE reason: Retain as non-core cytokinesis biology. supported_by: - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0000724 label: double-strand break repair via homologous recombination evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: &id009 summary: SPG15/ZFYVE26 silencing affected the DR-GFP homologous recombination readout in the KIAA0415/SPG48 DNA-repair study, but this is not the principal proteostasis function. action: KEEP_AS_NON_CORE reason: Retain as non-core experimental DNA-repair context with the caveat that the better-supported core is endolysosomal membrane remodeling. supported_by: - reference_id: PMID:20613862 supporting_text: KIAA0415 interacts with SPG11, SPG15 - reference_id: PMID:20613862 supporting_text: significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15 - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: *id001 - term: id: GO:0007040 label: lysosome organization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: &id006 summary: Lysosome organization is the best current GO representation for spastizin-dependent ALR, free lysosome regeneration, lysosomal tubulation, and AP5-SPG11-SPG15 membrane remodeling. action: ACCEPT reason: Retain as a core proteostasis function; GO lacks a more specific autophagic lysosome reformation term in the review file. supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - reference_id: PMID:37871017 supporting_text: Spastizin and AP5Z1 contribute to regulate tubular lysosome formation - reference_id: PMID:37871017 supporting_text: indirectly regulates spastizin recruitment at lysosomes - term: id: GO:0030496 label: midbody evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: *id002 - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: *id003 - term: id: GO:0046872 label: metal ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The FYVE zinc finger implies structural metal binding, but this annotation is less informative than the experimentally supported PI3P-binding function. action: MODIFY reason: Use PI3P binding as the informative molecular-function term for the FYVE domain rather than retaining generic metal ion binding as a core function. proposed_replacement_terms: - id: GO:0032266 label: phosphatidylinositol-3-phosphate binding supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23825025 qualifier: enables review: summary: The AP-5/SPG11/SPG15 interaction is real, but generic protein binding obscures the coat-like endolysosomal membrane-organization role. action: MODIFY reason: Replace generic binding with lysosomal membrane organization and lysosome organization for the AP5-SPG11-SPG15 coat context. proposed_replacement_terms: - id: GO:0097212 label: lysosomal membrane organization - id: GO:0007040 label: lysosome organization supported_by: - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:37871017 qualifier: enables review: summary: The spastizin/AP5Z1/motor-protein interaction context is biologically meaningful, but the informative function is tubular lysosome formation and lysosome trafficking organization rather than generic protein binding. action: MODIFY reason: Replace generic binding with lysosome organization/lysosomal membrane organization. proposed_replacement_terms: - id: GO:0007040 label: lysosome organization - id: GO:0097212 label: lysosomal membrane organization supported_by: - reference_id: PMID:37871017 supporting_text: Spastizin and AP5Z1 contribute to regulate tubular lysosome formation - reference_id: PMID:37871017 supporting_text: indirectly regulates spastizin recruitment at lysosomes - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40175557 qualifier: enables review: summary: The 2025 structural paper supports a membrane-remodeling AP5-SPG11-SPG15 complex, not generic protein binding as an informative molecular function. action: MODIFY reason: Replace generic binding with membrane bending, lysosomal membrane organization, and lysosome organization. proposed_replacement_terms: - id: GO:0097753 label: membrane bending - id: GO:0097212 label: lysosomal membrane organization - id: GO:0007040 label: lysosome organization supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:40175557 qualifier: enables review: summary: Identical protein binding is less informative than the structural mechanism showing SPG11-SPG15/AP5 assembly driving PI3P-dependent membrane remodeling. action: MODIFY reason: Replace the generic self/complex-binding term with membrane bending and lysosomal membrane organization. proposed_replacement_terms: - id: GO:0097753 label: membrane bending - id: GO:0097212 label: lysosomal membrane organization supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0005764 label: lysosome evidence_type: IPI original_reference_id: PMID:25365221 qualifier: located_in review: &id004 summary: Lysosome is a core compartment for ZFYVE26/spastizin because ALR and AP5-SPG11-SPG15 membrane remodeling depend on spastizin recruitment to lysosomal/endolysosomal membranes. action: ACCEPT reason: Retain as a core endolysosomal location. supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - term: id: GO:0005770 label: late endosome evidence_type: IPI original_reference_id: PMID:40175557 qualifier: located_in review: &id005 summary: Late endosome is supported by AP-5/SPG11/SPG15 colocalization and the 2025 AP5-SPG11-SPG15 late-endosome membrane sorting/remodeling model. action: ACCEPT reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 machinery. supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - term: id: GO:0097212 label: lysosomal membrane organization evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: summary: Lysosomal membrane organization is directly supported by the AP5-SPG11-SPG15 PI3P-dependent membrane-remodeling study and ALR/tubulation evidence. action: ACCEPT reason: Retain as a core proteostasis process. supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - term: id: GO:0097753 label: membrane bending evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: summary: Membrane bending is supported by the AP5-SPG11-SPG15 structural study; the lysosomal/endolysosomal context should remain explicit in curation notes. action: ACCEPT reason: Retain as a core membrane-remodeling process coupled to lysosomal membrane organization. supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - term: id: GO:0005764 label: lysosome evidence_type: NAS original_reference_id: PMID:40175557 qualifier: located_in review: *id004 - term: id: GO:0005770 label: late endosome evidence_type: NAS original_reference_id: PMID:40175557 qualifier: located_in review: *id005 - term: id: GO:0007040 label: lysosome organization evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: *id006 - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:25365221 qualifier: located_in review: *id004 - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:25365221 qualifier: located_in review: summary: The cached PMID:25365221 abstract does not verify the early-endosome row, but independent spastizin literature reports partial early-endosome colocalization. action: KEEP_AS_NON_CORE reason: Retain as a non-core reported compartment rather than a defining proteostasis location. supported_by: - reference_id: PMID:24030950 supporting_text: co-localizes partially with early endosomes, the endoplasmic reticulum, microtubules and vesicles involved in protein trafficking - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: The seeded paper's accessible abstract does not verify early endosome, but independent Brain abstract reports partial early-endosome colocalization. - term: id: GO:0005770 label: late endosome evidence_type: IDA original_reference_id: PMID:25365221 qualifier: located_in review: *id005 - term: id: GO:0007040 label: lysosome organization evidence_type: IDA original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: *id006 - term: id: GO:0019901 label: protein kinase binding evidence_type: IDA original_reference_id: PMID:25365221 qualifier: enables review: summary: The available cached PMID:25365221 text supports ALR, PI3P-dependent lysosomal targeting, and lysosomal tubulation, but it does not provide enough evidence to verify protein kinase binding for ZFYVE26. action: UNDECIDED reason: Leave undecided pending access to the underlying full-text/MGI evidence for this specific molecular-function annotation. supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: The `GO:0019901 protein kinase binding` annotation from PMID:25365221 could not be verified from the cached abstract. - term: id: GO:1905037 label: autophagosome organization evidence_type: IDA original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: &id007 summary: The cited ALR paper primarily supports lysosome reformation/tubulation after autophagy rather than organization of autophagosomes themselves. action: MODIFY reason: Replace with lysosome organization for the PMID:25365221 ALR evidence. Add autophagosome maturation separately from PMID:24030950, which directly supports that term. proposed_replacement_terms: - id: GO:0007040 label: lysosome organization - id: GO:0097352 label: autophagosome maturation supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:24030950 supporting_text: spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation - reference_id: PMID:24030950 supporting_text: impairment of autophagosome maturation and an accumulation of immature autophagosomes - term: id: GO:0007040 label: lysosome organization evidence_type: IMP original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: *id006 - term: id: GO:1905037 label: autophagosome organization evidence_type: IMP original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: *id007 - term: id: GO:0032465 label: regulation of cytokinesis evidence_type: IMP original_reference_id: PMID:20208530 qualifier: involved_in review: *id008 - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Lysosomal membrane association is supported by lysosomal membrane proteomics and is consistent with the AP5-SPG11-SPG15 lysosomal membrane remodeling model. action: ACCEPT reason: Retain as a broad core endolysosomal membrane location. supported_by: - reference_id: PMID:17897319 supporting_text: identified 58 proteins, known to reside at least partially in the lysosomal membrane - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - term: id: GO:0000724 label: double-strand break repair via homologous recombination evidence_type: IMP original_reference_id: PMID:20613862 qualifier: involved_in review: *id009 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20613862 qualifier: enables review: summary: The SPG15 interaction evidence supports membership in an HSP/DNA-repair-associated complex, but generic protein binding is not useful as a retained molecular function. action: MARK_AS_OVER_ANNOTATED reason: Do not retain generic protein binding; the same paper already supports a non-core HR-DSBR process annotation. supported_by: - reference_id: PMID:20613862 supporting_text: KIAA0415 interacts with SPG11, SPG15 - reference_id: PMID:20613862 supporting_text: significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15 - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20208530 qualifier: enables review: summary: The KIF13A/TTC19/FYVE-CENT interactions support recruitment of cytokinesis machinery to the PI3P-positive midbody rather than generic protein binding as a useful function. action: MODIFY reason: Replace generic binding with regulation of cytokinesis for this evidence source. proposed_replacement_terms: - id: GO:0032465 label: regulation of cytokinesis supported_by: - reference_id: PMID:20208530 supporting_text: PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) - reference_id: PMID:20208530 supporting_text: Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A - reference_id: PMID:20208530 supporting_text: cytokinesis arrest and an increased number of binucleate and multinucleate cells - reference_id: file:human/ZFYVE26/ZFYVE26-notes.md supporting_text: generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:20208530 qualifier: located_in review: *id001 - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:20208530 qualifier: located_in review: *id002 - term: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding evidence_type: IDA original_reference_id: PMID:20208530 qualifier: enables review: *id003 - term: id: GO:0097352 label: autophagosome maturation evidence_type: IMP original_reference_id: PMID:24030950 qualifier: involved_in review: summary: Spastizin has direct autophagosome-maturation evidence through patient-cell and silencing experiments showing impaired maturation and immature autophagosome accumulation when spastizin is absent or mutant. action: NEW reason: Add autophagosome maturation as a distinct annotation from the ALR/lysosome-organization rows, because PMID:24030950 explicitly supports maturation of autophagosomes. supported_by: - reference_id: PMID:24030950 supporting_text: spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation - reference_id: PMID:24030950 supporting_text: impairment of autophagosome maturation and an accumulation of immature autophagosomes references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:20208530 title: PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. findings: [] - id: PMID:20613862 title: A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. findings: [] - id: PMID:23825025 title: Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15. findings: [] - id: PMID:25365221 title: Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. findings: [] - id: PMID:37871017 title: Spatacsin regulates directionality of lysosome trafficking by promoting the degradation of its partner AP5Z1. findings: [] - id: PMID:40175557 title: Structural basis for membrane remodeling by the AP5-SPG11-SPG15 complex. findings: [] - id: PMID:24030950 title: Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. findings: [] core_functions: - molecular_function: id: GO:0032266 label: phosphatidylinositol-3-phosphate binding description: PI3P-dependent recruitment and membrane remodeling by spastizin as part of the AP5-SPG11-SPG15 machinery, supporting autophagic lysosome reformation, lysosomal tubulation/membrane organization, membrane bending, and autophagosome maturation. directly_involved_in: - id: GO:0007040 label: lysosome organization - id: GO:0097212 label: lysosomal membrane organization - id: GO:0097753 label: membrane bending - id: GO:0097352 label: autophagosome maturation locations: - id: GO:0005764 label: lysosome - id: GO:0005770 label: late endosome - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain - reference_id: PMID:24030950 supporting_text: spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation - reference_id: PMID:24030950 supporting_text: impairment of autophagosome maturation and an accumulation of immature autophagosomes proposed_new_terms: - proposed_name: autophagic lysosome reformation proposed_definition: A lysosome organization process in which autolysosomal membranes tubulate and regenerate functional lysosomes after autophagic degradation. justification: ZFYVE26/spastizin and SPG11/spatacsin are described as pivotal for ALR and essential for initiation of lysosomal tubulation, but the review must currently use broader lysosome organization and lysosomal membrane organization terms. proposed_parent: id: GO:0007040 label: lysosome organization supported_by: - reference_id: PMID:25365221 supporting_text: pivotal for autophagic lysosome reformation (ALR) - reference_id: PMID:25365221 supporting_text: Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate - reference_id: PMID:25365221 supporting_text: Loss of spastizin or spatacsin resulted in depletion of free lysosomes - reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - proposed_name: AP5-SPG11-SPG15 complex-mediated lysosomal membrane remodeling proposed_definition: A lysosomal membrane organization process in which the AP5-SPG11-SPG15 complex binds PI3P-positive membranes, senses curvature, and remodels membranes during autolysosome tubulation. justification: The 2025 structural study supports PI3P binding, curvature sensing, and membrane remodeling by the AP5-SPG11-SPG15 complex, but current GO terms separate membrane bending from the specific lysosomal complex/process context. proposed_parent: id: GO:0097212 label: lysosomal membrane organization supported_by: - reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - reference_id: PMID:40175557 supporting_text: essential for the initiation of autolysosome tubulation - reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - reference_id: PMID:23825025 supporting_text: SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain suggested_questions: - question: Should GO add an autophagic lysosome reformation term under lysosome organization so ZFYVE26/SPG15, SPG11, PIP5K1B, KIF5B, and related ALR factors can be annotated without overusing broad lysosome organization? experts: - Li Yu - Craig Blackstone - GO biological process editors - question: Should spastizin-mediated autophagosome maturation through Beclin 1-UVRAG-Rubicon be curated separately from AP5-SPG11-SPG15-dependent ALR/lysosomal membrane remodeling? experts: - Maria Teresa Bassi - Li Yu - GO autophagy editors - question: Should the HR-DSBR annotation for ZFYVE26/SPG15 remain as a non-core process, or is the DR-GFP evidence too indirect relative to the stronger SPG48/KIAA0415 focus of PMID:20613862? experts: - Andreas Ladurner - Craig Blackstone - GO DNA repair editors suggested_experiments: - description: Rescue ZFYVE26/SPG15-deficient cells with FYVE-domain and AP5/SPG11-interface mutants, then quantify starvation-refeeding ALR, free lysosome regeneration, lysosomal tubulation, and autophagosome maturation. experiment_type: genetic rescue/live-cell lysosome and autophagy imaging hypothesis: PI3P binding and AP5-SPG11-SPG15 complex assembly are required for spastizin-dependent ALR and lysosomal membrane organization. - description: Measure membrane curvature sensing and remodeling by purified AP5-SPG11-SPG15 complexes containing SPG15 FYVE-domain or complex-interface mutants on PI3P-containing liposomes. experiment_type: in vitro membrane remodeling/structural biochemistry hypothesis: Spastizin contributes directly to PI3P-dependent membrane remodeling as part of the AP5-SPG11-SPG15 complex. - description: Separate cytokinesis, autophagosome maturation, and ALR outputs using domain-specific ZFYVE26 mutants in matched midbody, Beclin 1-UVRAG-Rubicon, and lysosomal tubulation assays. experiment_type: domain-function epistasis hypothesis: ZFYVE26 has separable PI3P-dependent cytokinesis and proteostasis functions that should not be collapsed into one broad GO process.