id: Q96JI7 gene_symbol: SPG11 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- SPG11 encodes spatacsin, a large cytoplasmic/peripheral membrane-associated protein that functions with SPG15/spastizin and AP-5 in endolysosomal membrane remodeling. The strongest protein-homeostasis evidence supports a core role in autophagic lysosome reformation, lysosomal tubulation, lysosome membrane recycling, and ER-linked lysosome trafficking/organization. SPG11 also has supported neuronal axonal/synaptic transport contexts, but its principal described cellular role is endolysosomal membrane remodeling. alternative_products: - name: '1' id: Q96JI7-1 - name: '2' id: Q96JI7-2 sequence_note: VSP_025483, VSP_025484 - name: '3' id: Q96JI7-3 sequence_note: VSP_045347 existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor. action: ACCEPT reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context. supported_by: - &id007 reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Cytoplasm, cytosol - &id008 reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Mainly cytoplasmic - &id015 reference_id: PMID:37871017 supporting_text: spatacsin is an ER-resident protein regulating the formation of tubular lysosomes - &id016 reference_id: PMID:37871017 supporting_text: spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking - term: id: GO:0007409 label: axonogenesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Axonogenesis is plausible from orthology and disease biology, but human experimental evidence more directly supports axonal maintenance/transport defects than a core developmental axonogenesis role. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal/developmental context rather than the proteostasis core function. supported_by: &id004 - &id001 reference_id: PMID:24794856 supporting_text: spatacsin was located in axons and dendrites - &id002 reference_id: PMID:24794856 supporting_text: reduction in the anterograde vesicle trafficking indicative of impaired axonal transport - &id003 reference_id: PMID:24794856 supporting_text: SPG11 is implicated in axonal maintenance and cargo trafficking - term: id: GO:0007268 label: chemical synaptic transmission evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Chemical synaptic transmission is a plausible neuronal consequence of SPG11 dysfunction, but the direct evidence centers on synaptic vesicle/cargo transport defects. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal phenotype/context. supported_by: - *id001 - *id002 - *id003 - &id005 reference_id: PMID:24794856 supporting_text: colocalized with cytoskeletal and synaptic vesicle (SV) markers - &id006 reference_id: PMID:24794856 supporting_text: SPG11 is implicated in axonal maintenance and cargo trafficking - term: id: GO:0008088 label: axo-dendritic transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Axo-dendritic transport is supported by impaired anterograde vesicle trafficking in SPG11-deficient neurons, but it is secondary to the endolysosomal proteostasis core. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal transport biology. supported_by: *id004 - term: id: GO:0030424 label: axon evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Axon localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: &id009 - reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Cell projection, axon - reference_id: PMID:24794856 supporting_text: spatacsin was located in axons and dendrites - term: id: GO:0030425 label: dendrite evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Dendrite localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: &id010 - reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Cell projection, dendrite - reference_id: PMID:24794856 supporting_text: spatacsin was located in axons and dendrites - term: id: GO:0045202 label: synapse evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: &id020 - *id005 - *id006 - term: id: GO:0048489 label: synaptic vesicle transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Synaptic vesicle transport is supported in neuronal models, but it is a secondary neuronal consequence/context for this proteostasis review. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal transport biology. supported_by: - *id001 - *id002 - *id003 - *id005 - *id006 - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Nucleus is reported in early localization evidence but UniProt notes that SPG11 is mainly cytoplasmic, and the proteostasis literature centers on endolysosomal remodeling. action: KEEP_AS_NON_CORE reason: Retain as a non-core reported location rather than a defining SPG11 location. supported_by: &id025 - reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Nucleus - reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Mainly cytoplasmic - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes. action: ACCEPT reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations. supported_by: &id021 - *id007 - *id008 - term: id: GO:0030424 label: axon evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Axon localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: *id009 - term: id: GO:0030425 label: dendrite evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Dendrite localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: *id010 - 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 endolysosomal coat/scaffold role. action: MODIFY reason: Replace generic binding with lysosomal membrane organization for the AP5-SPG11-SPG15 coat-like complex context. proposed_replacement_terms: - &id012 id: GO:0097212 label: lysosomal membrane organization - &id011 id: GO:0007040 label: lysosome organization supported_by: - &id030 reference_id: PMID:23825025 supporting_text: the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15 - &id031 reference_id: PMID:23825025 supporting_text: AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment - &id032 reference_id: PMID:23825025 supporting_text: AP-5, SPG15, and SPG11 form a coat-like complex - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: This proteome-scale interactome evidence is too generic to define an SPG11 molecular function. action: MARK_AS_OVER_ANNOTATED reason: Avoid retaining GO:0005515 when no SPG11-specific mechanism is curated from the evidence. supported_by: - &id013 reference_id: file:human/SPG11/SPG11-notes.md supporting_text: Proteome-scale interactome rows from PMID:25416956 and PMID:33961781 are insufficiently informative for core GO curation without a mechanism specific to SPG11 - &id014 reference_id: file:human/SPG11/SPG11-notes.md supporting_text: Generic `GO:0005515 protein binding` is overused in this record. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29949766 qualifier: enables review: summary: The dynamin interaction is mechanistic, but the informative function is lysosome membrane recycling/lysosome organization. action: MODIFY reason: Replace generic protein binding with lysosome organization/lysosomal membrane organization. proposed_replacement_terms: - *id011 - *id012 supported_by: &id036 - &id026 reference_id: PMID:29949766 supporting_text: spatacsin, which is required for lysosome recycling - &id027 reference_id: PMID:29949766 supporting_text: spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: This proteome-scale interactome evidence is too generic to define an SPG11 molecular function. action: MARK_AS_OVER_ANNOTATED reason: Avoid retaining GO:0005515 when no SPG11-specific mechanism is curated from the evidence. supported_by: - *id013 - *id014 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36096339 qualifier: enables review: summary: PKA/14-3-3-dependent interaction regulates spatacsin trafficking, but generic protein binding is not an informative GO function for SPG11. action: MARK_AS_OVER_ANNOTATED reason: Do not retain generic protein binding as a core molecular function; capture this as regulatory context in notes/questions instead. supported_by: - &id023 reference_id: PMID:36096339 supporting_text: identified a subset of 14-3-3 proteins as physiological interactors of spatacsin - &id024 reference_id: PMID:36096339 supporting_text: The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955 - *id014 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:37871017 qualifier: enables review: summary: The AP5Z1/spastizin interaction/regulation evidence is real, but the useful function is ER-linked tubular lysosome formation and lysosome trafficking directionality. action: MODIFY reason: Replace generic binding with lysosome organization, which better captures the functional outcome. proposed_replacement_terms: - *id011 supported_by: &id019 - *id015 - *id016 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40175557 qualifier: enables review: summary: The structural paper defines AP5-SPG11-SPG15 assembly and membrane remodeling, not a useful standalone generic protein-binding function. action: MODIFY reason: Replace generic binding with membrane bending and lysosomal membrane organization. proposed_replacement_terms: - &id017 id: GO:0097753 label: membrane bending - *id012 supported_by: &id018 - &id028 reference_id: PMID:40175557 supporting_text: SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes - &id029 reference_id: PMID:40175557 supporting_text: AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:40175557 qualifier: enables review: summary: The homomeric/complex assembly evidence is less informative than the demonstrated AP5-SPG11-SPG15 membrane remodeling function. action: MODIFY reason: Replace identical protein binding with membrane bending and lysosomal membrane organization. proposed_replacement_terms: - *id017 - *id012 supported_by: *id018 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor. action: ACCEPT reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context. supported_by: - *id007 - *id008 - *id015 - *id016 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Endoplasmic reticulum is supported by recent endogenous localization and functional lysosome-trafficking evidence. action: ACCEPT reason: Retain ER as a core functional location for SPG11-dependent tubular lysosome formation and ER-lysosome trafficking regulation. supported_by: *id019 - term: id: GO:0045202 label: synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: *id020 - term: id: GO:0005730 label: nucleolus evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Nucleolus is a weak high-throughput localization relative to the stronger cytoplasmic, ER, late-endolysosomal, and neuronal-process evidence. action: MARK_AS_OVER_ANNOTATED reason: Do not treat nucleolus as an informative SPG11 location without stronger gene-specific mechanistic evidence. supported_by: - &id022 reference_id: file:human/SPG11/SPG11-notes.md supporting_text: Nucleolus and plasma membrane HPA rows are weak - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes. action: ACCEPT reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations. supported_by: *id021 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Plasma membrane is not a defining SPG11 location; PKA/14-3-3 work mentions trafficking from plasma membrane to intracellular space, but core function is endolysosomal/ER membrane remodeling. action: KEEP_AS_NON_CORE reason: Retain only as non-core trafficking/regulatory context. supported_by: - *id022 - *id023 - *id024 - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:17322883 qualifier: located_in review: summary: Nucleus is reported in early localization evidence but UniProt notes that SPG11 is mainly cytoplasmic, and the proteostasis literature centers on endolysosomal remodeling. action: KEEP_AS_NON_CORE reason: Retain as a non-core reported location rather than a defining SPG11 location. supported_by: *id025 - term: id: GO:0005764 label: lysosome evidence_type: IPI original_reference_id: PMID:25365221 qualifier: located_in review: summary: Lysosome is a supported core compartment for SPG11-dependent ALR, lysosome membrane recycling, and AP5-SPG11-SPG15 membrane remodeling. action: ACCEPT reason: Retain as a core endolysosomal location/process context. supported_by: - &id033 reference_id: PMID:25365221 supporting_text: the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR) - &id034 reference_id: PMID:25365221 supporting_text: spastizin and spatacsin were essential components for the initiation of lysosomal tubulation - *id026 - *id027 - *id028 - *id029 - term: id: GO:0005770 label: late endosome evidence_type: IPI original_reference_id: PMID:40175557 qualifier: located_in review: summary: Late endosome is supported by AP5-SPG11-SPG15 membrane sorting/remodeling evidence and AP-5/SPG11/SPG15 colocalization. action: ACCEPT reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 complex. supported_by: - *id028 - *id029 - *id030 - *id031 - *id032 - term: id: GO:0097212 label: lysosomal membrane organization evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: summary: Lysosomal membrane organization directly captures SPG11-dependent AP5-SPG11-SPG15 membrane remodeling and ALR/tubulation. action: ACCEPT reason: Retain as a core process annotation for SPG11 in the proteostasis network. supported_by: - *id028 - *id029 - *id033 - *id034 - term: id: GO:0097753 label: membrane bending evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: summary: Membrane bending is directly supported by the AP5-SPG11-SPG15 structural/mechanistic study, though the lysosomal context should be retained in curation notes. action: ACCEPT reason: Retain as a core membrane-remodeling process coupled to lysosomal membrane organization. supported_by: *id018 - term: id: GO:0005764 label: lysosome evidence_type: NAS original_reference_id: PMID:40175557 qualifier: located_in review: summary: Lysosome is a supported core compartment for SPG11-dependent ALR, lysosome membrane recycling, and AP5-SPG11-SPG15 membrane remodeling. action: ACCEPT reason: Retain as a core endolysosomal location/process context. supported_by: - *id033 - *id034 - *id026 - *id027 - *id028 - *id029 - term: id: GO:0005770 label: late endosome evidence_type: NAS original_reference_id: PMID:40175557 qualifier: located_in review: summary: Late endosome is supported by AP5-SPG11-SPG15 membrane sorting/remodeling evidence and AP-5/SPG11/SPG15 colocalization. action: ACCEPT reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 complex. supported_by: - *id028 - *id029 - *id030 - *id031 - *id032 - term: id: GO:0007040 label: lysosome organization evidence_type: NAS original_reference_id: PMID:40175557 qualifier: involved_in review: summary: Lysosome organization is the best current GO representation of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation. action: ACCEPT reason: Retain as a core SPG11 function in the proteostasis network. supported_by: - *id033 - *id034 - *id026 - *id027 - *id015 - *id016 - *id028 - *id029 - term: id: GO:0007040 label: lysosome organization evidence_type: IDA original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: summary: Lysosome organization is the best current GO representation of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation. action: ACCEPT reason: Retain as a core SPG11 function in the proteostasis network. supported_by: - *id033 - *id034 - *id026 - *id027 - *id015 - *id016 - *id028 - *id029 - term: id: GO:0007040 label: lysosome organization evidence_type: IMP original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: summary: Lysosome organization is the best current GO representation of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation. action: ACCEPT reason: Retain as a core SPG11 function in the proteostasis network. supported_by: - *id033 - *id034 - *id026 - *id027 - *id015 - *id016 - *id028 - *id029 - 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 and lysosomal tubulation, but it does not provide enough evidence to verify protein kinase binding for SPG11. action: UNDECIDED reason: Leave undecided pending access to the underlying MGI/full-text evidence for this specific molecular-function annotation. supported_by: - *id033 - *id034 - reference_id: file:human/SPG11/SPG11-notes.md supporting_text: GO:1905037 autophagosome organization is less precise - term: id: GO:1905037 label: autophagosome organization evidence_type: IDA original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: summary: The cited ALR evidence concerns reformation/tubulation of lysosomes after autophagy, not organization of autophagosomes themselves. action: MODIFY reason: Replace with lysosome organization, which better matches depletion of free lysosomes, autolysosome accumulation, and failure of ALR. proposed_replacement_terms: - *id011 supported_by: &id035 - *id033 - *id034 - term: id: GO:1905037 label: autophagosome organization evidence_type: IMP original_reference_id: PMID:25365221 qualifier: acts_upstream_of_or_within review: summary: The cited ALR evidence concerns reformation/tubulation of lysosomes after autophagy, not organization of autophagosomes themselves. action: MODIFY reason: Replace with lysosome organization, which better matches depletion of free lysosomes, autolysosome accumulation, and failure of ALR. proposed_replacement_terms: - *id011 supported_by: *id035 - term: id: GO:0005829 label: cytosol evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes. action: ACCEPT reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations. supported_by: *id021 - term: id: GO:0045202 label: synapse evidence_type: IDA original_reference_id: PMID:24794856 qualifier: located_in review: summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal localization. supported_by: *id020 - term: id: GO:0008088 label: axo-dendritic transport evidence_type: IMP original_reference_id: PMID:24794856 qualifier: involved_in review: summary: Axo-dendritic transport is supported by impaired anterograde vesicle trafficking in SPG11-deficient neurons, but it is secondary to the endolysosomal proteostasis core. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal transport biology. supported_by: *id004 - term: id: GO:0007268 label: chemical synaptic transmission evidence_type: IMP original_reference_id: PMID:24794856 qualifier: involved_in review: summary: Chemical synaptic transmission is a plausible neuronal consequence of SPG11 dysfunction, but the direct evidence centers on synaptic vesicle/cargo transport defects. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal phenotype/context. supported_by: - *id001 - *id002 - *id003 - *id005 - *id006 - term: id: GO:0048489 label: synaptic vesicle transport evidence_type: IMP original_reference_id: PMID:24794856 qualifier: involved_in review: summary: Synaptic vesicle transport is supported in neuronal models, but it is a secondary neuronal consequence/context for this proteostasis review. action: KEEP_AS_NON_CORE reason: Retain as non-core neuronal transport biology. supported_by: - *id001 - *id002 - *id003 - *id005 - *id006 - 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 proteomic evidence and is consistent with SPG11-dependent lysosomal membrane remodeling/recycling. action: ACCEPT reason: Retain as a core endolysosomal membrane location, while noting that recent work also supports ER-associated pools. supported_by: - reference_id: PMID:17897319 supporting_text: identified 58 proteins, known to reside at least partially in the lysosomal membrane - *id028 - *id029 - *id015 - *id016 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21545838 qualifier: located_in review: summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor. action: ACCEPT reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context. supported_by: - *id007 - *id008 - *id015 - *id016 - term: id: GO:0031410 label: cytoplasmic vesicle evidence_type: IDA original_reference_id: PMID:21545838 qualifier: located_in review: summary: Cytoplasmic vesicle localization is supported by early antibody localization, but the informative locations are ER, late endosome, lysosome, and lysosomal membrane. action: KEEP_AS_NON_CORE reason: Retain as non-core/broad vesicular context rather than a defining location. supported_by: - reference_id: PMID:21545838 supporting_text: diffuse punctate, cytoplasmic - reference_id: PMID:21545838 supporting_text: protein-trafficking vesicles, endoplasmic reticulum and microtubules - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20613862 qualifier: enables review: summary: The interaction evidence supports AP5/SPG15/SPG11 network membership, but generic protein binding is not an informative retained function. action: MARK_AS_OVER_ANNOTATED reason: Use the later endolysosomal membrane-remodeling terms for the functional complex; do not retain generic binding as a function. supported_by: - reference_id: PMID:20613862 supporting_text: putative helicase that interacts with SPG11 and SPG15 - reference_id: file:human/SPG11/SPG11-uniprot.txt supporting_text: Interacts with AP5Z1, AP5B1, AP5S1 and ZFYVE26 - *id014 references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity 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:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:17322883 title: Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. 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:21545838 title: Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia. findings: [] - id: PMID:23825025 title: Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15. findings: [] - id: PMID:24794856 title: Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. findings: [] - id: PMID:25365221 title: Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:29949766 title: Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:36096339 title: Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins. 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: [] core_functions: - description: AP5-SPG11-SPG15-dependent organization and remodeling of late endosomal/lysosomal membranes during autophagic lysosome reformation, lysosomal tubulation, and lysosome membrane recycling. directly_involved_in: - *id011 - *id012 - *id017 locations: - id: GO:0005783 label: endoplasmic reticulum - id: GO:0005770 label: late endosome - id: GO:0005764 label: lysosome - id: GO:0005765 label: lysosomal membrane - id: GO:0005829 label: cytosol supported_by: - *id033 - *id034 - *id028 - *id029 - *id026 - *id027 - *id015 - *id016 - *id030 - *id031 - *id032 proposed_new_terms: - proposed_name: autophagic lysosome reformation proposed_definition: A lysosome organization process in which autolysosomal membranes tubulate and give rise to new functional lysosomes after autophagic degradation. justification: SPG11/spatacsin and SPG15/spastizin are described as pivotal for ALR and essential for initiation of lysosomal tubulation, but the review currently must use broader lysosome organization and lysosomal membrane organization terms. proposed_parent: *id011 supported_by: - *id033 - *id034 - reference_id: PMID:29949766 supporting_text: tubulation occurs in autolysosomes to promote the reformation of new functional lysosomes, a process called autophagic lysosome reformation (ALR) - proposed_name: lysosome membrane recycling proposed_definition: A lysosome organization process that recycles lysosomal membrane components from autolysosomes or lysosome-derived carriers to regenerate functional lysosomes. justification: SPG11/spatacsin is required for lysosome membrane recycling and recruits dynamin for this process, but existing GO terms are broader than the specific recycling step. proposed_parent: *id012 supported_by: *id036 suggested_questions: - question: Should GO add an autophagic lysosome reformation term under lysosome organization so SPG11, SPG15, KIF5B, PIP5K1B, and related ALR factors can be annotated without overusing broad lysosome organization? experts: - Li Yu - Craig Blackstone - GO biological process editors - question: Should SPG11 be annotated to a complex/scaffold molecular function, or should AP5-SPG11-SPG15 activity be represented only through biological process terms such as lysosomal membrane organization and membrane bending? experts: - Margaret Robinson - Yong Ma - GO molecular function editors - question: What is the best GO representation for SPG11-dependent AP5Z1 degradation and control of lysosome trafficking directionality in neurons? experts: - Frederic Darios - Giovanni Stevanin - GO biological process editors suggested_experiments: - description: Rescue SPG11-null cells with SPG11 mutants defective in AP-5/SPG15 binding and quantify ALR after starvation-refeeding, including autolysosome tubulation, free lysosome regeneration, and lysosome membrane recycling. experiment_type: genetic rescue/live-cell lysosome imaging hypothesis: AP5-SPG11-SPG15 complex assembly is required for SPG11-dependent autophagic lysosome reformation and lysosomal membrane organization. - description: Measure membrane curvature sensing and remodeling by purified AP5-SPG11-SPG15 complexes with SPG11 interface mutants on PI3P-containing liposomes. experiment_type: in vitro membrane remodeling/structural biochemistry hypothesis: SPG11 contributes directly to PI3P-dependent membrane remodeling as part of the AP5-SPG11-SPG15 complex. - description: Track lysosome movement in polarized neurons after perturbing SPG11, AP5Z1 degradation, KIF13A, and dynein/dynactin interactions while separately scoring axonal synaptic vesicle transport. experiment_type: neuronal live imaging/rescue epistasis hypothesis: SPG11-dependent ER/lysosome membrane remodeling controls lysosome trafficking directionality independently from broader synaptic vesicle transport phenotypes.