Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005813 centrosome	IBA GO_REF:0000033	KEEP AS NON CORE	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. Reason: Retain as non-core localization tied to the midbody/cytokinesis context. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0030496 midbody	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Midbody localization is directly supported and mechanistically linked to PI3P-dependent cytokinesis, but it is non-core for this proteostasis-focused review. Reason: Retain as non-core localization tied to cytokinesis. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0032266 phosphatidylinositol-3-phosphate binding	IBA GO_REF:0000033	ACCEPT	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. Reason: Retain PI3P binding as the core molecular function that links spastizin to both midbody biology and the proteostasis-relevant endolysosomal membrane-remodeling machinery. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0032465 regulation of cytokinesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: ZFYVE26/FYVE-CENT has direct midbody/cytokinesis evidence, but this is not the core proteostasis function emphasized by the PN review. Reason: Retain as a supported non-core cytokinesis role while prioritizing ALR/endolysosomal membrane organization as the proteostasis core. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0000281 mitotic cytokinesis	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Mitotic cytokinesis is supported by the FYVE-CENT midbody paper, but it is a non-core role relative to ZFYVE26/spastizin proteostasis biology. Reason: Retain as non-core cytokinesis biology. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0000724 double-strand break repair via homologous recombination	IEA GO_REF:0000002	KEEP AS NON CORE	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. Reason: Retain as non-core experimental DNA-repair context with the caveat that the better-supported core is endolysosomal membrane remodeling. Supporting Evidence: PMID:20613862 KIAA0415 interacts with SPG11, SPG15 PMID:20613862 significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15
GO:0005813 centrosome	IEA GO_REF:0000044	KEEP AS NON CORE	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. Reason: Retain as non-core localization tied to the midbody/cytokinesis context. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0007040 lysosome organization	IEA GO_REF:0000117	ACCEPT	Summary: Lysosome organization is the best current GO representation for spastizin-dependent ALR, free lysosome regeneration, lysosomal tubulation, and AP5-SPG11-SPG15 membrane remodeling. Reason: Retain as a core proteostasis function; GO lacks a more specific autophagic lysosome reformation term in the review file. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:37871017 Spastizin and AP5Z1 contribute to regulate tubular lysosome formation PMID:37871017 indirectly regulates spastizin recruitment at lysosomes
GO:0030496 midbody	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Midbody localization is directly supported and mechanistically linked to PI3P-dependent cytokinesis, but it is non-core for this proteostasis-focused review. Reason: Retain as non-core localization tied to cytokinesis. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0032266 phosphatidylinositol-3-phosphate binding	IEA GO_REF:0000002	ACCEPT	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. Reason: Retain PI3P binding as the core molecular function that links spastizin to both midbody biology and the proteostasis-relevant endolysosomal membrane-remodeling machinery. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0046872 metal ion binding	IEA GO_REF:0000002	MODIFY	Summary: The FYVE zinc finger implies structural metal binding, but this annotation is less informative than the experimentally supported PI3P-binding function. 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 replacements: phosphatidylinositol-3-phosphate binding Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0005515 protein binding	IPI PMID:23825025 Interaction between AP-5 and the hereditary spastic parapleg...	MODIFY	Summary: The AP-5/SPG11/SPG15 interaction is real, but generic protein binding obscures the coat-like endolysosomal membrane-organization role. Reason: Replace generic binding with lysosomal membrane organization and lysosome organization for the AP5-SPG11-SPG15 coat context. Proposed replacements: lysosomal membrane organization lysosome organization Supporting Evidence: PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0005515 protein binding	IPI PMID:37871017 Spatacsin regulates directionality of lysosome trafficking b...	MODIFY	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. Reason: Replace generic binding with lysosome organization/lysosomal membrane organization. Proposed replacements: lysosome organization lysosomal membrane organization Supporting Evidence: PMID:37871017 Spastizin and AP5Z1 contribute to regulate tubular lysosome formation PMID:37871017 indirectly regulates spastizin recruitment at lysosomes file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0005515 protein binding	IPI PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	MODIFY	Summary: The 2025 structural paper supports a membrane-remodeling AP5-SPG11-SPG15 complex, not generic protein binding as an informative molecular function. Reason: Replace generic binding with membrane bending, lysosomal membrane organization, and lysosome organization. Proposed replacements: membrane bending lysosomal membrane organization lysosome organization Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0042802 identical protein binding	IPI PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	MODIFY	Summary: Identical protein binding is less informative than the structural mechanism showing SPG11-SPG15/AP5 assembly driving PI3P-dependent membrane remodeling. Reason: Replace the generic self/complex-binding term with membrane bending and lysosomal membrane organization. Proposed replacements: membrane bending lysosomal membrane organization Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0005764 lysosome	IPI PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	ACCEPT	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. Reason: Retain as a core endolysosomal location. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0005770 late endosome	IPI PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	Summary: Late endosome is supported by AP-5/SPG11/SPG15 colocalization and the 2025 AP5-SPG11-SPG15 late-endosome membrane sorting/remodeling model. Reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 machinery. Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0097212 lysosomal membrane organization	NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	Summary: Lysosomal membrane organization is directly supported by the AP5-SPG11-SPG15 PI3P-dependent membrane-remodeling study and ALR/tubulation evidence. Reason: Retain as a core proteostasis process. Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0097753 membrane bending	NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	Summary: Membrane bending is supported by the AP5-SPG11-SPG15 structural study; the lysosomal/endolysosomal context should remain explicit in curation notes. Reason: Retain as a core membrane-remodeling process coupled to lysosomal membrane organization. Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation
GO:0005764 lysosome	NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	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. Reason: Retain as a core endolysosomal location. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0005770 late endosome	NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	Summary: Late endosome is supported by AP-5/SPG11/SPG15 colocalization and the 2025 AP5-SPG11-SPG15 late-endosome membrane sorting/remodeling model. Reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 machinery. Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0007040 lysosome organization	NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP...	ACCEPT	Summary: Lysosome organization is the best current GO representation for spastizin-dependent ALR, free lysosome regeneration, lysosomal tubulation, and AP5-SPG11-SPG15 membrane remodeling. Reason: Retain as a core proteostasis function; GO lacks a more specific autophagic lysosome reformation term in the review file. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:37871017 Spastizin and AP5Z1 contribute to regulate tubular lysosome formation PMID:37871017 indirectly regulates spastizin recruitment at lysosomes
GO:0005764 lysosome	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	ACCEPT	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. Reason: Retain as a core endolysosomal location. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0005769 early endosome	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	KEEP AS NON CORE	Summary: The cached PMID:25365221 abstract does not verify the early-endosome row, but independent spastizin literature reports partial early-endosome colocalization. Reason: Retain as a non-core reported compartment rather than a defining proteostasis location. Supporting Evidence: PMID:24030950 co-localizes partially with early endosomes, the endoplasmic reticulum, microtubules and vesicles involved in protein trafficking file:human/ZFYVE26/ZFYVE26-notes.md The seeded paper's accessible abstract does not verify early endosome, but independent Brain abstract reports partial early-endosome colocalization.
GO:0005770 late endosome	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	ACCEPT	Summary: Late endosome is supported by AP-5/SPG11/SPG15 colocalization and the 2025 AP5-SPG11-SPG15 late-endosome membrane sorting/remodeling model. Reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 machinery. Supporting Evidence: PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0007040 lysosome organization	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	ACCEPT	Summary: Lysosome organization is the best current GO representation for spastizin-dependent ALR, free lysosome regeneration, lysosomal tubulation, and AP5-SPG11-SPG15 membrane remodeling. Reason: Retain as a core proteostasis function; GO lacks a more specific autophagic lysosome reformation term in the review file. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:37871017 Spastizin and AP5Z1 contribute to regulate tubular lysosome formation PMID:37871017 indirectly regulates spastizin recruitment at lysosomes
GO:0019901 protein kinase binding	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	UNDECIDED	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. Reason: Leave undecided pending access to the underlying full-text/MGI evidence for this specific molecular-function annotation. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation file:human/ZFYVE26/ZFYVE26-notes.md The `GO:0019901 protein kinase binding` annotation from PMID:25365221 could not be verified from the cached abstract.
GO:1905037 autophagosome organization	IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	MODIFY	Summary: The cited ALR paper primarily supports lysosome reformation/tubulation after autophagy rather than organization of autophagosomes themselves. Reason: Replace with lysosome organization for the PMID:25365221 ALR evidence. Add autophagosome maturation separately from PMID:24030950, which directly supports that term. Proposed replacements: lysosome organization autophagosome maturation Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:24030950 spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation PMID:24030950 impairment of autophagosome maturation and an accumulation of immature autophagosomes
GO:0007040 lysosome organization	IMP PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	ACCEPT	Summary: Lysosome organization is the best current GO representation for spastizin-dependent ALR, free lysosome regeneration, lysosomal tubulation, and AP5-SPG11-SPG15 membrane remodeling. Reason: Retain as a core proteostasis function; GO lacks a more specific autophagic lysosome reformation term in the review file. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:37871017 Spastizin and AP5Z1 contribute to regulate tubular lysosome formation PMID:37871017 indirectly regulates spastizin recruitment at lysosomes
GO:1905037 autophagosome organization	IMP PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ...	MODIFY	Summary: The cited ALR paper primarily supports lysosome reformation/tubulation after autophagy rather than organization of autophagosomes themselves. Reason: Replace with lysosome organization for the PMID:25365221 ALR evidence. Add autophagosome maturation separately from PMID:24030950, which directly supports that term. Proposed replacements: lysosome organization autophagosome maturation Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:24030950 spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation PMID:24030950 impairment of autophagosome maturation and an accumulation of immature autophagosomes
GO:0032465 regulation of cytokinesis	IMP PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr...	KEEP AS NON CORE	Summary: ZFYVE26/FYVE-CENT has direct midbody/cytokinesis evidence, but this is not the core proteostasis function emphasized by the PN review. Reason: Retain as a supported non-core cytokinesis role while prioritizing ALR/endolysosomal membrane organization as the proteostasis core. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Lysosomal membrane association is supported by lysosomal membrane proteomics and is consistent with the AP5-SPG11-SPG15 lysosomal membrane remodeling model. Reason: Retain as a broad core endolysosomal membrane location. Supporting Evidence: PMID:17897319 identified 58 proteins, known to reside at least partially in the lysosomal membrane PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
GO:0000724 double-strand break repair via homologous recombination	IMP PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ...	KEEP AS NON CORE	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. Reason: Retain as non-core experimental DNA-repair context with the caveat that the better-supported core is endolysosomal membrane remodeling. Supporting Evidence: PMID:20613862 KIAA0415 interacts with SPG11, SPG15 PMID:20613862 significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15
GO:0005515 protein binding	IPI PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ...	MARK AS OVER ANNOTATED	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. Reason: Do not retain generic protein binding; the same paper already supports a non-core HR-DSBR process annotation. Supporting Evidence: PMID:20613862 KIAA0415 interacts with SPG11, SPG15 PMID:20613862 significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15 file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0005515 protein binding	IPI PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr...	MODIFY	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. Reason: Replace generic binding with regulation of cytokinesis for this evidence source. Proposed replacements: regulation of cytokinesis Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells file:human/ZFYVE26/ZFYVE26-notes.md generic `protein binding` rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source
GO:0005813 centrosome	IDA PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr...	KEEP AS NON CORE	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. Reason: Retain as non-core localization tied to the midbody/cytokinesis context. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0030496 midbody	IDA PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr...	KEEP AS NON CORE	Summary: Midbody localization is directly supported and mechanistically linked to PI3P-dependent cytokinesis, but it is non-core for this proteostasis-focused review. Reason: Retain as non-core localization tied to cytokinesis. Supporting Evidence: PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0032266 phosphatidylinositol-3-phosphate binding	IDA PMID:20208530 PtdIns(3)P controls cytokinesis through KIF13A-mediated recr...	ACCEPT	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. Reason: Retain PI3P binding as the core molecular function that links spastizin to both midbody biology and the proteostasis-relevant endolysosomal membrane-remodeling machinery. Supporting Evidence: PMID:25365221 pivotal for autophagic lysosome reformation (ALR) PMID:25365221 Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate PMID:25365221 Loss of spastizin or spatacsin resulted in depletion of free lysosomes PMID:25365221 spastizin and spatacsin were essential components for the initiation of lysosomal tubulation PMID:40175557 AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro PMID:40175557 essential for the initiation of autolysosome tubulation PMID:23825025 the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 PMID:23825025 AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment PMID:23825025 SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain PMID:20208530 PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26) PMID:20208530 Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A PMID:20208530 cytokinesis arrest and an increased number of binucleate and multinucleate cells
GO:0097352 autophagosome maturation	IMP PMID:24030950 Defective autophagy in spastizin mutated patients with hered...	NEW	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. Reason: Add autophagosome maturation as a distinct annotation from the ALR/lysosome-organization rows, because PMID:24030950 explicitly supports maturation of autophagosomes. Supporting Evidence: PMID:24030950 spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation PMID:24030950 impairment of autophagosome maturation and an accumulation of immature autophagosomes

Core Functions

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.

Molecular Function:

phosphatidylinositol-3-phosphate binding

Directly Involved In:

lysosome organization lysosomal membrane organization membrane bending autophagosome maturation

Cellular Locations:

lysosome late endosome lysosomal membrane

Supporting Evidence:

PMID:25365221
pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate
PMID:25365221
Loss of spastizin or spatacsin resulted in depletion of free lysosomes
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
PMID:40175557
essential for the initiation of autolysosome tubulation
PMID:23825025
the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15
PMID:23825025
AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment
PMID:23825025
SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain
PMID:24030950
spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation
PMID:24030950
impairment of autophagosome maturation and an accumulation of immature autophagosomes

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:20208530

PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody.

PMID:20613862

A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.

PMID:23825025

Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15.

PMID:25365221

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.

PMID:37871017

Spatacsin regulates directionality of lysosome trafficking by promoting the degradation of its partner AP5Z1.

PMID:40175557

Structural basis for membrane remodeling by the AP5-SPG11-SPG15 complex.

PMID:24030950

Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15.

Suggested Experiments

Experiment: 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.

Hypothesis: PI3P binding and AP5-SPG11-SPG15 complex assembly are required for spastizin-dependent ALR and lysosomal membrane organization.

Type: genetic rescue/live-cell lysosome and autophagy imaging

Experiment: Measure membrane curvature sensing and remodeling by purified AP5-SPG11-SPG15 complexes containing SPG15 FYVE-domain or complex-interface mutants on PI3P-containing liposomes.

Hypothesis: Spastizin contributes directly to PI3P-dependent membrane remodeling as part of the AP5-SPG11-SPG15 complex.

Type: in vitro membrane remodeling/structural biochemistry

Experiment: Separate cytokinesis, autophagosome maturation, and ALR outputs using domain-specific ZFYVE26 mutants in matched midbody, Beclin 1-UVRAG-Rubicon, and lysosomal tubulation assays.

Hypothesis: ZFYVE26 has separable PI3P-dependent cytokinesis and proteostasis functions that should not be collapsed into one broad GO process.

Type: domain-function epistasis

📚 Additional Documentation

Notes

(ZFYVE26-notes.md)

ZFYVE26 notes

Review context

ZFYVE26 encodes spastizin/SPG15, a FYVE-domain protein in the AP5-SPG11-SPG15 endolysosomal machinery. In the Proteostasis Network browser it appears under autophagic lysosome reformation and class III PI3K complex 2/autophagosome maturation context. The PN row that lacks PMID mappings was treated as search/context only, not as direct evidence.

Falcon deep research was started with just deep-research-falcon human ZFYVE26 and timed out after 600 seconds with All providers failed. This notes file and the cached publications are the manual evidence record.

Evidence synthesis

The strongest proteostasis evidence places spastizin with spatacsin/SPG11 in autophagic lysosome reformation (ALR). The JCI abstract states that SPG15/spastizin and SPG11/spatacsin are "pivotal for autophagic lysosome reformation (ALR)", that lysosomal targeting of spastizin requires a FYVE domain binding PI3P, that loss of either protein depletes free lysosomes and causes autolysosome accumulation, and that they are essential for initiation of lysosomal tubulation [PMID:25365221 "pivotal for autophagic lysosome reformation (ALR)"; PMID:25365221 "Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate"; PMID:25365221 "Loss of spastizin or spatacsin resulted in depletion of free lysosomes"; PMID:25365221 "essential components for the initiation of lysosomal tubulation"]. This supports GO:0007040 lysosome organization and the existing lysosome/late-endosome locations as core, while GO:1905037 autophagosome organization is less precise for this paper than lysosome organization/ALR.

Structural evidence now directly supports the AP5-SPG11-SPG15 membrane remodeling model. The 2025 structural paper reports that SPG11-SPG15 cooperates with AP5 in late-endosome membrane sorting, and that the AP5-SPG11-SPG15 complex binds PI3P, senses curvature, drives membrane remodeling in vitro, and is essential for autolysosome tubulation [PMID:40175557 "AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro"; PMID:40175557 "essential for the initiation of autolysosome tubulation"]. This supports GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending, GO:0007040 lysosome organization, and PI3P binding as an informative molecular function.

The AP-5 interaction paper supports replacing generic protein-binding rows with endolysosomal membrane-organization terms: AP-5 subunits coimmunoprecipitate with SPG11/SPG15, all components colocalize on late endosomal/lysosomal compartments, and the authors propose a coat-like complex in which SPG15 docks the coat onto PI3P-containing membranes via its FYVE domain [PMID:23825025 "the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15"; PMID:23825025 "AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment"; PMID:23825025 "SPG15 facilitating the docking of the coat onto membranes by interacting with PI3P via its FYVE domain"].

Autophagosome maturation has independent support from the Brain abstract. It states that spastizin interacts with Beclin 1, associates with the Beclin 1-UVRAG-Rubicon complex, and is required for autophagosome maturation; spastizin-deficient or mutant cells accumulate immature autophagosomes [PMID:24030950 "spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation"; PMID:24030950 "impairment of autophagosome maturation and an accumulation of immature autophagosomes"]. This supports adding GO:0097352 autophagosome maturation as a new annotation, separate from the ALR/lysosome-organization evidence.

ZFYVE26 also has a well-supported cytokinesis role that should be retained as non-core for this proteostasis-focused review. Sagona et al. report that PI3P localizes to the midbody and recruits FYVE-CENT/ZFYVE26, that FYVE-CENT/TTC19 translocation from centrosome to midbody requires KIF13A, and that depletion of FYVE-CENT phenocopies PI3K-III/KIF13A/TTC19 depletion with cytokinesis arrest and multinucleated cells [PMID:20208530 "PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26)"; PMID:20208530 "Translocation of FYVE-CENT and TTC19 from the centrosome to the midbody requires another FYVE-CENT-interacting protein, the microtubule motor KIF13A"; PMID:20208530 "cytokinesis arrest and an increased number of binucleate and multinucleate cells"]. Thus centrosome, midbody, regulation of cytokinesis, and mitotic cytokinesis are real but non-core.

The HR-DSBR evidence is experimentally based but not a proteostasis core function. The genome-scale DNA repair paper identifies KIAA0415/SPG48 as the main focus, but also reports that KIAA0415 interacts with SPG11 and SPG15 and that SPG15 silencing reduces the DR-GFP homologous recombination readout [PMID:20613862 "KIAA0415 interacts with SPG11, SPG15"; PMID:20613862 "significant reduction of GFP positive cells were observed upon silencing of C20orf29 and SPG15"]. Keep homologous recombination DSB repair as non-core with the caveat that the better-supported proteostasis function is endolysosomal membrane remodeling.

The GO:0019901 protein kinase binding annotation from PMID:25365221 could not be verified from the cached abstract. Because the relevant full text is not locally accessible, this row should remain undecided rather than accepted.

The HDA lysosomal membrane row from PMID:17897319 is broad proteomics evidence. It can be retained as a broad location, but the stronger functional interpretation comes from the ALR/AP5-SPG11-SPG15 literature PMID:17897319.

Review decisions

Core: PI3P binding; AP5-SPG11-SPG15-dependent lysosomal/late endosomal membrane organization; membrane bending/remodeling; lysosome organization in ALR; autophagosome maturation.
Non-core: cytokinesis, midbody/centrosome localization, and possible HR-DSBR role.
Modify/replace: generic protein binding rows should be replaced by lysosome organization, lysosomal membrane organization, membrane bending, or regulation of cytokinesis depending on the source.
Undecided: protein kinase binding from PMID:25365221, due missing accessible evidence.

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

Moved out of the YAML description: cytokinesis and HR-DSBR roles were treated as non-core in this proteostasis-focused review, and generic protein-binding annotations should be replaced by specific membrane-organization, membrane-remodeling, or cytokinesis terms supported by the source publications.

Pn Notes

(ZFYVE26-pn-notes.md)

ZFYVE26 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q68DK2
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ZFYVE26/ZFYVE26-ai-review.yaml
AIGR review HTML: present - genes/human/ZFYVE26/ZFYVE26-ai-review.html
Gene notes: present - genes/human/ZFYVE26/ZFYVE26-notes.md
GOA TSV: present - genes/human/ZFYVE26/ZFYVE26-goa.tsv
UniProt record: present - genes/human/ZFYVE26/ZFYVE26-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ZFYVE26.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ZFYVE26.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 12; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 8; NEW: 1; UNDECIDED: 1

PN Consistency Summary

Consistency: Strongly consistent. Deep-research notes, review YAML, PN notes, and PN mappings all converge: core = PI3P-binding FYVE protein in AP5-SPG11-SPG15 endolysosomal membrane remodeling / ALR / autophagosome maturation. The PN note's "Beclin1-UVRAG-Rubicon… required for autophagosome maturation" matches the review's NEW GO:0097352 row. No contradictions.
PN story / NEW pressure: PN asserts (a) class III PI3K complex modulation — review correctly does NOT claim complex membership, using GO:0032266 PI3P binding + lysosome organization instead (matches PN's context_only decision); and (b) ALR with "specific function unknown." Review supplies the mechanism: GO:0007040, GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending, plus NEW GO:0097352 autophagosome maturation (OLS-verified real). ALR itself has no GO term (OLS search empty) — review's proposed_new_terms "autophagic lysosome reformation" under GO:0007040 is well-justified. Conclusion: NEW term (ALR) defensible; autophagosome maturation is a defensible ADD already in review; class-III-PI3K membership correctly NOT added.
Evidence alignment: Both PN refs are in the review. PN "Defective autophagy in spastizin… HSP type 15" = PMID:24030950 (autophagosome maturation); PN "spastizin and spatacsin mediate ALR" = PMID:25365221 (lysosome organization/ALR). Review adds PMID:40175557 (2025 structure), 23825025 (AP-5), 37871017, 20208530 the PN rows omit.
Verdict: Fully consistent; review enriches the PN "function unknown" ALR node with verified terms (GO:0097352 add + ALR proposed-new-term). Mappings sound; no demotions needed.

Full Consistency Review

UniProt: Q68DK2 (spastizin/SPG15/FYVE-CENT) · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: ALP|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Modulator of class 3 PI3K complex 2 activity and ALP|Autophagic lysosome reformation|Specific function… unknown ; PN-node mapping: PI3K-complex nodes all context_only/too_broad → GO:0035032 (class III PI3K complex), explicitly "should not project CC membership"; ALR group = no_mapping (unknown); ALR class = context_only → GO:0007040 lysosome organization.
Consistency: Strongly consistent. Deep-research notes, review YAML, PN notes, and PN mappings all converge: core = PI3P-binding FYVE protein in AP5-SPG11-SPG15 endolysosomal membrane remodeling / ALR / autophagosome maturation. The PN note's "Beclin1-UVRAG-Rubicon… required for autophagosome maturation" matches the review's NEW GO:0097352 row. No contradictions.
PN story / NEW pressure: PN asserts (a) class III PI3K complex modulation — review correctly does NOT claim complex membership, using GO:0032266 PI3P binding + lysosome organization instead (matches PN's context_only decision); and (b) ALR with "specific function unknown." Review supplies the mechanism: GO:0007040, GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending, plus NEW GO:0097352 autophagosome maturation (OLS-verified real). ALR itself has no GO term (OLS search empty) — review's proposed_new_terms "autophagic lysosome reformation" under GO:0007040 is well-justified. Conclusion: NEW term (ALR) defensible; autophagosome maturation is a defensible ADD already in review; class-III-PI3K membership correctly NOT added.
Mapping strategy: No change needed to PI3K nodes (context_only is right; precedent-aligned — narrower review terms, no spurious CC propagation). ALR group could be upgraded from no_mapping toward GO:0007040 lysosome organization (the review's accepted core, and the class-node target), but PN's "unknown specific function" caution is reasonable; review is narrower than the PN class-level GO:0007040, never broader.
Evidence alignment: Both PN refs are in the review. PN "Defective autophagy in spastizin… HSP type 15" = PMID:24030950 (autophagosome maturation); PN "spastizin and spatacsin mediate ALR" = PMID:25365221 (lysosome organization/ALR). Review adds PMID:40175557 (2025 structure), 23825025 (AP-5), 37871017, 20208530 the PN rows omit.
Verdict: Fully consistent; review enriches the PN "function unknown" ALR node with verified terms (GO:0097352 add + ALR proposed-new-term). Mappings sound; no demotions needed.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/ZFYVE26/ZFYVE26-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Class 3 PI3K complex 2, direct | Modulator of class 3 PI3K complex 2 activity

UniProt: Q68DK2
In branches: ALP
Notes: aka FYVE-CENT, SPG15, and spastizin. Spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking spastizin or with mutated forms of the protein, spastizin interaction with Beclin 1 is lost although the formation of the Beclin 1-UVRAG-Rubicon complex can still be observed. However, in these cells there is an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Also important in autophagic lysosomal reformation.
PN references (titles):
- Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15 | Brain | Oxford Academic (oup.com)
- JCI - Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Modulator of class 3 PI3K complex 2 activity
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagic lysosome reformation | Specific function in autophagic lysosome reformation unknown

UniProt: Q68DK2
In branches: ALP
Notes: aka FYVE-CENT, SPG15, and spastizin. Spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking spastizin or with mutated forms of the protein, spastizin interaction with Beclin 1 is lost although the formation of the Beclin 1-UVRAG-Rubicon complex can still be observed. However, in these cells there is an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Also important in autophagic lysosomal reformation.
PN references (titles):
- Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15 | Brain | Oxford Academic (oup.com)
- JCI - Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation
PN-node mapping records (path + ancestors):
- [group] Autophagy-Lysosome Pathway|Autophagic lysosome reformation|Specific function in autophagic lysosome reformation unknown
  status=no_mapping scope= GO=[]
  rationale: This PN group explicitly states that the specific role within autophagic lysosome reformation is unknown. That makes GO propagation unsafe until a narrower mechanistic interpretation is available.
- [class] Autophagy-Lysosome Pathway|Autophagic lysosome reformation
  status=context_only scope=too_broad_to_propagate GO=[GO:0007040 lysosome organization]
  rationale: Autophagic lysosome reformation is the lysosome-regeneration phase that follows autolysosome formation and cargo degradation. As a class, it is better aligned to lysosome organization than to generic autophagy, but the PN members are mechanistically mixed across membrane remodeling, tubulation, product efflux, and unknown late-stage roles, so class-level propagation would still over-annotate.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

ZFYVE26

Gene Description

Proposed New Ontology Terms

autophagic lysosome reformation

AP5-SPG11-SPG15 complex-mediated lysosomal membrane remodeling