SPG11

UniProt ID: Q96JI7
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Proposed New Ontology Terms

autophagic lysosome reformation

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.

Parent term: lysosome organization

Supporting Evidence:

lysosome membrane recycling

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.

Parent term: lysosomal membrane organization

Supporting Evidence:

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor.
Reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0007409 axonogenesis
IBA
GO_REF:0000033 		KEEP AS NON CORE
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.
Reason: Retain as non-core neuronal/developmental context rather than the proteostasis core function.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0007268 chemical synaptic transmission
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Chemical synaptic transmission is a plausible neuronal consequence of SPG11 dysfunction, but the direct evidence centers on synaptic vesicle/cargo transport defects.
Reason: Retain as non-core neuronal phenotype/context.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0008088 axo-dendritic transport
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Axo-dendritic transport is supported by impaired anterograde vesicle trafficking in SPG11-deficient neurons, but it is secondary to the endolysosomal proteostasis core.
Reason: Retain as non-core neuronal transport biology.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0030424 axon
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Axon localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cell projection, axon
PMID:24794856
spatacsin was located in axons and dendrites
GO:0030425 dendrite
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Dendrite localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cell projection, dendrite
PMID:24794856
spatacsin was located in axons and dendrites
GO:0045202 synapse
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0048489 synaptic vesicle transport
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Synaptic vesicle transport is supported in neuronal models, but it is a secondary neuronal consequence/context for this proteostasis review.
Reason: Retain as non-core neuronal transport biology.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0005634 nucleus
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Nucleus is reported in early localization evidence but UniProt notes that SPG11 is mainly cytoplasmic, and the proteostasis literature centers on endolysosomal remodeling.
Reason: Retain as a non-core reported location rather than a defining SPG11 location.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Nucleus
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
GO:0005829 cytosol
IEA
GO_REF:0000120 		ACCEPT
Summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes.
Reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
GO:0030424 axon
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Axon localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cell projection, axon
PMID:24794856
spatacsin was located in axons and dendrites
GO:0030425 dendrite
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Dendrite localization is supported in neurons, but it reflects the neuronal disease/transport context rather than the core ALR function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cell projection, dendrite
PMID:24794856
spatacsin was located in axons and dendrites
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 endolysosomal coat/scaffold role.
Reason: Replace generic binding with lysosomal membrane organization for the AP5-SPG11-SPG15 coat-like complex context.
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
AP-5, SPG15, and SPG11 form a coat-like complex
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		MARK AS OVER ANNOTATED
Summary: This proteome-scale interactome evidence is too generic to define an SPG11 molecular function.
Reason: Avoid retaining GO:0005515 when no SPG11-specific mechanism is curated from the evidence.
Supporting Evidence:
file:human/SPG11/SPG11-notes.md
Proteome-scale interactome rows from PMID:25416956 and PMID:33961781 are insufficiently informative for core GO curation without a mechanism specific to SPG11
file:human/SPG11/SPG11-notes.md
Generic `GO:0005515 protein binding` is overused in this record.
GO:0005515 protein binding
IPI
PMID:29949766
Inhibition of Lysosome Membrane Recycling Causes Accumulatio... 		MODIFY
Summary: The dynamin interaction is mechanistic, but the informative function is lysosome membrane recycling/lysosome organization.
Reason: Replace generic protein binding with lysosome organization/lysosomal membrane organization.
Supporting Evidence:
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: This proteome-scale interactome evidence is too generic to define an SPG11 molecular function.
Reason: Avoid retaining GO:0005515 when no SPG11-specific mechanism is curated from the evidence.
Supporting Evidence:
file:human/SPG11/SPG11-notes.md
Proteome-scale interactome rows from PMID:25416956 and PMID:33961781 are insufficiently informative for core GO curation without a mechanism specific to SPG11
file:human/SPG11/SPG11-notes.md
Generic `GO:0005515 protein binding` is overused in this record.
GO:0005515 protein binding
IPI
PMID:36096339
Cytosolic sequestration of spatacsin by Protein Kinase A and... 		MARK AS OVER ANNOTATED
Summary: PKA/14-3-3-dependent interaction regulates spatacsin trafficking, but generic protein binding is not an informative GO function for SPG11.
Reason: Do not retain generic protein binding as a core molecular function; capture this as regulatory context in notes/questions instead.
Supporting Evidence:
PMID:36096339
identified a subset of 14-3-3 proteins as physiological interactors of spatacsin
PMID:36096339
The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955
file:human/SPG11/SPG11-notes.md
Generic `GO:0005515 protein binding` is overused in this record.
GO:0005515 protein binding
IPI
PMID:37871017
Spatacsin regulates directionality of lysosome trafficking b... 		MODIFY
Summary: The AP5Z1/spastizin interaction/regulation evidence is real, but the useful function is ER-linked tubular lysosome formation and lysosome trafficking directionality.
Reason: Replace generic binding with lysosome organization, which better captures the functional outcome.
Proposed replacements: lysosome organization
Supporting Evidence:
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0005515 protein binding
IPI
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		MODIFY
Summary: The structural paper defines AP5-SPG11-SPG15 assembly and membrane remodeling, not a useful standalone generic protein-binding function.
Reason: Replace generic binding with membrane bending and lysosomal membrane organization.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0042802 identical protein binding
IPI
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		MODIFY
Summary: The homomeric/complex assembly evidence is less informative than the demonstrated AP5-SPG11-SPG15 membrane remodeling function.
Reason: Replace identical protein binding with membrane bending and lysosomal membrane organization.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		ACCEPT
Summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor.
Reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000107 		ACCEPT
Summary: Endoplasmic reticulum is supported by recent endogenous localization and functional lysosome-trafficking evidence.
Reason: Retain ER as a core functional location for SPG11-dependent tubular lysosome formation and ER-lysosome trafficking regulation.
Supporting Evidence:
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0045202 synapse
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0005730 nucleolus
IDA
GO_REF:0000052 		MARK AS OVER ANNOTATED
Summary: Nucleolus is a weak high-throughput localization relative to the stronger cytoplasmic, ER, late-endolysosomal, and neuronal-process evidence.
Reason: Do not treat nucleolus as an informative SPG11 location without stronger gene-specific mechanistic evidence.
Supporting Evidence:
file:human/SPG11/SPG11-notes.md
Nucleolus and plasma membrane HPA rows are weak
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes.
Reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
GO:0005886 plasma membrane
IDA
GO_REF:0000052 		KEEP AS NON CORE
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.
Reason: Retain only as non-core trafficking/regulatory context.
Supporting Evidence:
file:human/SPG11/SPG11-notes.md
Nucleolus and plasma membrane HPA rows are weak
PMID:36096339
identified a subset of 14-3-3 proteins as physiological interactors of spatacsin
PMID:36096339
The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955
GO:0005634 nucleus
EXP
PMID:17322883
Mutations in SPG11, encoding spatacsin, are a major cause of... 		KEEP AS NON CORE
Summary: Nucleus is reported in early localization evidence but UniProt notes that SPG11 is mainly cytoplasmic, and the proteostasis literature centers on endolysosomal remodeling.
Reason: Retain as a non-core reported location rather than a defining SPG11 location.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Nucleus
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
GO:0005764 lysosome
IPI
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate ... 		ACCEPT
Summary: Lysosome is a supported core compartment for SPG11-dependent ALR, lysosome membrane recycling, and AP5-SPG11-SPG15 membrane remodeling.
Reason: Retain as a core endolysosomal location/process context.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0005770 late endosome
IPI
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		ACCEPT
Summary: Late endosome is supported by AP5-SPG11-SPG15 membrane sorting/remodeling evidence and AP-5/SPG11/SPG15 colocalization.
Reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 complex.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
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
AP-5, SPG15, and SPG11 form a coat-like complex
GO:0097212 lysosomal membrane organization
NAS
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		ACCEPT
Summary: Lysosomal membrane organization directly captures SPG11-dependent AP5-SPG11-SPG15 membrane remodeling and ALR/tubulation.
Reason: Retain as a core process annotation for SPG11 in the proteostasis network.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
GO:0097753 membrane bending
NAS
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		ACCEPT
Summary: Membrane bending is directly supported by the AP5-SPG11-SPG15 structural/mechanistic study, though the lysosomal context should be retained in curation notes.
Reason: Retain as a core membrane-remodeling process coupled to lysosomal membrane organization.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0005764 lysosome
NAS
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		ACCEPT
Summary: Lysosome is a supported core compartment for SPG11-dependent ALR, lysosome membrane recycling, and AP5-SPG11-SPG15 membrane remodeling.
Reason: Retain as a core endolysosomal location/process context.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0005770 late endosome
NAS
PMID:40175557
Structural basis for membrane remodeling by the AP5-SPG11-SP... 		ACCEPT
Summary: Late endosome is supported by AP5-SPG11-SPG15 membrane sorting/remodeling evidence and AP-5/SPG11/SPG15 colocalization.
Reason: Retain as a core endolysosomal compartment for the AP5-SPG11-SPG15 complex.
Supporting Evidence:
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
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
AP-5, SPG15, and SPG11 form a coat-like complex
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 of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation.
Reason: Retain as a core SPG11 function in the proteostasis network.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0007040 lysosome organization
IDA
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate ... 		ACCEPT
Summary: Lysosome organization is the best current GO representation of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation.
Reason: Retain as a core SPG11 function in the proteostasis network.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
GO:0007040 lysosome organization
IMP
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate ... 		ACCEPT
Summary: Lysosome organization is the best current GO representation of SPG11-dependent ALR, lysosome membrane recycling, and tubular lysosome formation.
Reason: Retain as a core SPG11 function in the proteostasis network.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
PMID:29949766
spatacsin, which is required for lysosome recycling
PMID:29949766
spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
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 and lysosomal tubulation, but it does not provide enough evidence to verify protein kinase binding for SPG11.
Reason: Leave undecided pending access to the underlying MGI/full-text evidence for this specific molecular-function annotation.
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
file:human/SPG11/SPG11-notes.md
GO:1905037 autophagosome organization is less precise
GO:1905037 autophagosome organization
IDA
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate ... 		MODIFY
Summary: The cited ALR evidence concerns reformation/tubulation of lysosomes after autophagy, not organization of autophagosomes themselves.
Reason: Replace with lysosome organization, which better matches depletion of free lysosomes, autolysosome accumulation, and failure of ALR.
Proposed replacements: lysosome organization
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
GO:1905037 autophagosome organization
IMP
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate ... 		MODIFY
Summary: The cited ALR evidence concerns reformation/tubulation of lysosomes after autophagy, not organization of autophagosomes themselves.
Reason: Replace with lysosome organization, which better matches depletion of free lysosomes, autolysosome accumulation, and failure of ALR.
Proposed replacements: lysosome organization
Supporting Evidence:
PMID:25365221
the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
PMID:25365221
spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
GO:0005829 cytosol
ISS
GO_REF:0000024 		ACCEPT
Summary: Cytosol is supported by UniProt/HPA-style localization and is compatible with a large cytoplasmic scaffold associated with endolysosomal membranes.
Reason: Retain cytosol as a core broad location, not as a substitute for the more specific endolysosomal/ER locations.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
GO:0045202 synapse
IDA
PMID:24794856
Dysfunction of spatacsin leads to axonal pathology in SPG11-... 		KEEP AS NON CORE
Summary: Synapse localization is supported by neuronal/synaptosome evidence, but it is secondary to the lysosome reformation and membrane-remodeling function.
Reason: Retain as non-core neuronal localization.
Supporting Evidence:
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0008088 axo-dendritic transport
IMP
PMID:24794856
Dysfunction of spatacsin leads to axonal pathology in SPG11-... 		KEEP AS NON CORE
Summary: Axo-dendritic transport is supported by impaired anterograde vesicle trafficking in SPG11-deficient neurons, but it is secondary to the endolysosomal proteostasis core.
Reason: Retain as non-core neuronal transport biology.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0007268 chemical synaptic transmission
IMP
PMID:24794856
Dysfunction of spatacsin leads to axonal pathology in SPG11-... 		KEEP AS NON CORE
Summary: Chemical synaptic transmission is a plausible neuronal consequence of SPG11 dysfunction, but the direct evidence centers on synaptic vesicle/cargo transport defects.
Reason: Retain as non-core neuronal phenotype/context.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0048489 synaptic vesicle transport
IMP
PMID:24794856
Dysfunction of spatacsin leads to axonal pathology in SPG11-... 		KEEP AS NON CORE
Summary: Synaptic vesicle transport is supported in neuronal models, but it is a secondary neuronal consequence/context for this proteostasis review.
Reason: Retain as non-core neuronal transport biology.
Supporting Evidence:
PMID:24794856
spatacsin was located in axons and dendrites
PMID:24794856
reduction in the anterograde vesicle trafficking indicative of impaired axonal transport
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
PMID:24794856
colocalized with cytoskeletal and synaptic vesicle (SV) markers
PMID:24794856
SPG11 is implicated in axonal maintenance and cargo trafficking
GO:0005765 lysosomal membrane
HDA
PMID:17897319
Integral and associated lysosomal membrane proteins. 		ACCEPT
Summary: Lysosomal membrane association is supported by proteomic evidence and is consistent with SPG11-dependent lysosomal membrane remodeling/recycling.
Reason: Retain as a core endolysosomal membrane location, while noting that recent work also supports ER-associated pools.
Supporting Evidence:
PMID:17897319
identified 58 proteins, known to reside at least partially in the lysosomal membrane
PMID:40175557
SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
PMID:40175557
AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0005737 cytoplasm
IDA
PMID:21545838
Cellular distribution and subcellular localization of spatac... 		ACCEPT
Summary: SPG11/spatacsin is mainly cytoplasmic and functions as a cytoplasmic/peripheral membrane-associated endolysosomal remodeling factor.
Reason: Retain cytoplasm as a core broad location, while relying on ER, late endosome, lysosome, and lysosomal membrane terms for more specific context.
Supporting Evidence:
file:human/SPG11/SPG11-uniprot.txt
Cytoplasm, cytosol
file:human/SPG11/SPG11-uniprot.txt
Mainly cytoplasmic
PMID:37871017
spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
PMID:37871017
spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
GO:0031410 cytoplasmic vesicle
IDA
PMID:21545838
Cellular distribution and subcellular localization of spatac... 		KEEP AS NON CORE
Summary: Cytoplasmic vesicle localization is supported by early antibody localization, but the informative locations are ER, late endosome, lysosome, and lysosomal membrane.
Reason: Retain as non-core/broad vesicular context rather than a defining location.
Supporting Evidence:
PMID:21545838
diffuse punctate, cytoplasmic
PMID:21545838
protein-trafficking vesicles, endoplasmic reticulum and microtubules
GO:0005515 protein binding
IPI
PMID:20613862
A genome-scale DNA repair RNAi screen identifies SPG48 as a ... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence supports AP5/SPG15/SPG11 network membership, but generic protein binding is not an informative retained function.
Reason: Use the later endolysosomal membrane-remodeling terms for the functional complex; do not retain generic binding as a function.
Supporting Evidence:
PMID:20613862
putative helicase that interacts with SPG11 and SPG15
file:human/SPG11/SPG11-uniprot.txt
Interacts with AP5Z1, AP5B1, AP5S1 and ZFYVE26
file:human/SPG11/SPG11-notes.md
Generic `GO:0005515 protein binding` is overused in this record.

Core Functions

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:
lysosome organization lysosomal membrane organization membrane bending
Cellular Locations:
endoplasmic reticulum late endosome lysosome lysosomal membrane cytosol
Supporting Evidence:
  • PMID:25365221
    the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)
  • PMID:25365221
    spastizin and spatacsin were essential components for the initiation of lysosomal tubulation
  • PMID:40175557
    SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes
  • PMID:40175557
    AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro
  • PMID:29949766
    spatacsin, which is required for lysosome recycling
  • PMID:29949766
    spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes
  • PMID:37871017
    spatacsin is an ER-resident protein regulating the formation of tubular lysosomes
  • PMID:37871017
    spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking
  • 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
    AP-5, SPG15, and SPG11 form a coat-like complex

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
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:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:17322883
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.
PMID:17897319
Integral and associated lysosomal membrane proteins.
PMID:20613862
A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.
PMID:21545838
Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia.
PMID:23825025
Interaction between AP-5 and the hereditary spastic paraplegia proteins SPG11 and SPG15.
PMID:24794856
Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia.
PMID:25365221
Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:29949766
Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:36096339
Cytosolic sequestration of spatacsin by Protein Kinase A and 14-3-3 proteins.
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.

Suggested Questions for Experts

Q: 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?

Suggested experts: Li Yu, Craig Blackstone, GO biological process editors

Q: 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?

Suggested experts: Margaret Robinson, Yong Ma, GO molecular function editors

Q: What is the best GO representation for SPG11-dependent AP5Z1 degradation and control of lysosome trafficking directionality in neurons?

Suggested experts: Frederic Darios, Giovanni Stevanin, GO biological process editors

Suggested Experiments

Experiment: 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.

Hypothesis: AP5-SPG11-SPG15 complex assembly is required for SPG11-dependent autophagic lysosome reformation and lysosomal membrane organization.

Type: genetic rescue/live-cell lysosome imaging

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

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

Type: in vitro membrane remodeling/structural biochemistry

Experiment: Track lysosome movement in polarized neurons after perturbing SPG11, AP5Z1 degradation, KIF13A, and dynein/dynactin interactions while separately scoring axonal synaptic vesicle transport.

Hypothesis: SPG11-dependent ER/lysosome membrane remodeling controls lysosome trafficking directionality independently from broader synaptic vesicle transport phenotypes.

Type: neuronal live imaging/rescue epistasis

📚 Additional Documentation

Notes

(SPG11-notes.md)

SPG11 review notes

Review focus: proteostasis network context places SPG11/spatacsin under autophagic lysosome reformation (ALR), with the specific PN row marked no_mapping. For curation, this row is search context unless backed by primary literature. SPG11 has direct primary support for ALR and lysosome membrane remodeling, so the review should center on lysosome organization/lysosomal membrane organization rather than generic protein binding or broad neuronal phenotypes.

Core lysosome reformation and membrane remodeling

  • The JCI ALR paper directly supports SPG11/spatacsin as an ALR factor: "the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR)" and "spastizin and spatacsin were essential components for the initiation of lysosomal tubulation" PMID:25365221.
  • This supports retaining GO:0007040 lysosome organization as core. GO:1905037 autophagosome organization is less precise, because the described defect is generation/reformation of lysosomes after autophagy, not organization of autophagosomes themselves [PMID:25365221 "Loss of spastizin or spatacsin resulted in depletion of free lysosomes" / "an accumulation of autolysosomes, reflecting a failure in ALR"].
  • The 2025 structure paper supports a membrane-remodeling mechanism for the AP5-SPG11-SPG15 complex: "SPG11-SPG15 can cooperate with the fifth adaptor protein complex (AP5) involved in membrane sorting of late endosomes" and "AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro" PMID:40175557. This supports GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending, late endosome/lysosome context, and modifying generic protein-binding rows from that reference.
  • Lysosome membrane recycling is independently supported in neuronal disease models: "spatacsin, which is required for lysosome recycling" and "spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes" PMID:29949766. This is core proteostasis/endolysosomal evidence, but the seeded protein binding annotation from this paper should be replaced with lysosome organization/lysosomal membrane organization, not retained as generic binding.
  • Recent work also supports ER-linked lysosome trafficking/tubulation: "spatacsin is an ER-resident protein regulating the formation of tubular lysosomes" and "spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking" PMID:37871017. This supports ER/late-endolysosomal context and lysosome organization, but generic protein binding remains uninformative.

AP-5/SPG15 complex context

  • AP-5/SPG11/SPG15 interaction is real and mechanistically important: "the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15" and "AP-5, SPG11, and SPG15 colocalize on a late endosomal/lysosomal compartment" PMID:23825025. The same abstract proposes a coat-like complex in which SPG11 forms a scaffold. Generic protein binding should therefore be modified to endolysosomal membrane organization or kept only as non-core interaction context.
  • UniProt summarizes a narrower interaction set: "Interacts with AP5Z1, AP5B1, AP5S1 and ZFYVE26" [file:human/SPG11/SPG11-uniprot.txt]. This supports interaction provenance but not a useful GO molecular function term.
  • The original SPG48/DNA-repair screen paper contains SPG11-LAP immunoprecipitation methods and described a putative helicase interacting with SPG11/SPG15, but this is not SPG11's proteostasis core function PMID:20613862.

Neuronal transport and disease biology

  • Neuronal transport evidence is strong but should be non-core in this proteostasis review. Spatacsin was found in axons/dendrites and synaptosomes, and knockdown/patient-derived neurons showed vesicle trafficking defects [PMID:24794856 "spatacsin was located in axons and dendrites" / "reduction in the anterograde vesicle trafficking indicative of impaired axonal transport" / "SPG11 is implicated in axonal maintenance and cargo trafficking"].
  • IBA annotations for axonogenesis, chemical synaptic transmission, axo-dendritic transport, synapse, and synaptic vesicle transport are plausible by orthology and human evidence, but they are secondary phenotypes/contexts relative to ALR and lysosome organization.

Locations

  • UniProt supports cytosol/cytoplasm and neuronal processes: "Cytoplasm, cytosol", "Nucleus", "Cell projection, axon", and "Cell projection, dendrite", with note "Mainly cytoplasmic" [file:human/SPG11/SPG11-uniprot.txt].
  • Murmu 2011 supports cytoplasmic vesicle/ER/microtubule colocalization: "diffuse punctate, cytoplasmic" and "partially co-localized with multiple organelles, particularly with protein-trafficking vesicles, endoplasmic reticulum and microtubules" PMID:21545838. These locations are useful but broad; ER is now better supported as a functional location by PMID:37871017.
  • Nucleolus and plasma membrane HPA rows are weak relative to the lysosome/ER/neural-process evidence and should be kept non-core or marked over-annotated unless stronger gene-specific evidence is found.

Generic binding annotations

  • Generic GO:0005515 protein binding is overused in this record. The curation guideline says to avoid protein binding when a more informative term captures function. For SPG11, AP5/SPG15/dynamin/14-3-3 interactions are better captured as lysosome organization, lysosomal membrane organization, membrane bending, lysosome trafficking/regulation, or kept as non-core regulatory context.
  • The PKA/14-3-3 paper supports regulatory interaction but not SPG11 core function: "identified a subset of 14-3-3 proteins as physiological interactors of spatacsin" and "The interaction is modulated by Protein Kinase A (PKA)-dependent phosphorylation of spatacsin at Ser1955" PMID:36096339.
  • Proteome-scale interactome rows from PMID:25416956 and PMID:33961781 are insufficiently informative for core GO curation without a mechanism specific to SPG11; they should be marked over-annotated.

Deep research

  • Falcon deep research was started with just deep-research-falcon human SPG11 during this review and timed out after 600s with All providers failed; no SPG11-deep-research-falcon.md evidence was available for this review.

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: existing GOA appropriately includes lysosome organization, lysosomal membrane organization, membrane bending, late endosome/lysosome locations, ER, and cytoplasmic locations; neuronal axonal/synaptic transport annotations are supported but non-core in this proteostasis-focused review; generic protein-binding annotations should be replaced by or subordinated to more informative endolysosomal membrane-organization processes.

Pn Notes

(SPG11-pn-notes.md)

SPG11 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q96JI7
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-pr-1217 (PR 1217)
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 18; MARK_AS_OVER_ANNOTATED: 5; MODIFY: 7; UNDECIDED: 1

PN Consistency Summary

  • Consistency: Consistent. Notes, review YAML and PN all center on ALR/lysosomal membrane remodeling. Review correctly treats the PN row as search context (its own notes say "this row is search context unless backed by primary literature"). No contradictions; neuronal axonal/synaptic rows kept as non-core, matching the deep-research framing.
  • PN story / NEW pressure: PN's "ALR" story IS captured in GOA-equivalent terms the review accepts/adds: GO:0007040 lysosome organization, GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending (all verified real, used as core). The review additionally proposes two genuinely new terms — "autophagic lysosome reformation" (parent GO:0007040) and "lysosome membrane recycling" (parent GO:0097212) — as proposed_new_terms, which is the right altitude since no exact ALR GO term exists. Conclude: already captured at the available altitude; ADD only as proposed_new_terms (not mintable now).
  • Evidence alignment: Strong overlap. PN cites the JCI ALR paper = review's PMID:25365221 (ACCEPT, core). Review adds extensive endolysosomal evidence (PMID:40175557 structure, 29949766, 37871017, 23825025) PN does not list — divergence is enrichment, not conflict.
  • Verdict: Fully consistent, well-curated. No edits needed.

Full Consistency Review

  • UniProt: Q96JI7 (spatacsin) · batch: proteostasis-pr-1217 · review status: COMPLETE
  • PN placement: Autophagy-Lysosome Pathway → Autophagic lysosome reformation → "Specific function in autophagic lysosome reformation unknown" (1 row, ALP) ; PN-node mapping: group=no_mapping (function explicitly "unknown"); class (ALR)=context_only/too_broad_to_propagate→GO:0007040 lysosome organization; branch=no_mapping. No GO propagates to SPG11 from PN.
  • Consistency: Consistent. Notes, review YAML and PN all center on ALR/lysosomal membrane remodeling. Review correctly treats the PN row as search context (its own notes say "this row is search context unless backed by primary literature"). No contradictions; neuronal axonal/synaptic rows kept as non-core, matching the deep-research framing.
  • PN story / NEW pressure: PN's "ALR" story IS captured in GOA-equivalent terms the review accepts/adds: GO:0007040 lysosome organization, GO:0097212 lysosomal membrane organization, GO:0097753 membrane bending (all verified real, used as core). The review additionally proposes two genuinely new terms — "autophagic lysosome reformation" (parent GO:0007040) and "lysosome membrane recycling" (parent GO:0097212) — as proposed_new_terms, which is the right altitude since no exact ALR GO term exists. Conclude: already captured at the available altitude; ADD only as proposed_new_terms (not mintable now).
  • Mapping strategy: This gene does not change the node. The PN class-level GO:0007040 exactly matches the review's chosen core term, so node status (no_mapping leaf, context_only class) is appropriate; no broader/narrower conflict.
  • Evidence alignment: Strong overlap. PN cites the JCI ALR paper = review's PMID:25365221 (ACCEPT, core). Review adds extensive endolysosomal evidence (PMID:40175557 structure, 29949766, 37871017, 23825025) PN does not list — divergence is enrichment, not conflict.
  • Verdict: Fully consistent, well-curated. No edits needed.

PN Dossier Context

  • review_batch: proteostasis-pr-1217
  • review_yaml: genes/human/SPG11/SPG11-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagic lysosome reformation | Specific function in autophagic lysosome reformation unknown

  • UniProt: Q96JI7
  • In branches: ALP
  • Notes: Important for autophagic-lysosome reformation
  • PN references (titles):
    • 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: 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.