C9orf72 is a DENN-family regulator of small-GTPase-dependent membrane trafficking. Its long product forms a stable complex with SMCR8 and WDR41 that helps control GTPase cycling and endolysosomal homeostasis. C9orf72 also recognizes active Rab1A to recruit autophagy-initiation machinery, and purified C9orf72 has been reported to promote Rab39A nucleotide exchange upstream of HOPS-dependent autophagosome–lysosome fusion. The protein is predominantly cytoplasmic, with nutrient-dependent lysosomal association and enrichment in neuronal presynaptic compartments. It also influences stress-granule responses and neuronal actin dynamics. Pathogenic intronic repeat expansions can reduce normal protein expression while generating toxic repeat RNA and dipeptide-repeat products; these are distinct from the normal protein and its alternative products.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000932 P-body | IDA PMID:27037575 C9ORF72 Regulates Stress Granule Formation and Its Deficienc... | KEEP AS NON CORE | Summary: C9orf72 is reported in processing bodies. Reason: The complete PMID:27037575 abstract explicitly reports localization of normal C9orf72 to P-bodies and stress-dependent redistribution. Retain this contextual compartment while recognizing that the original imaging, reagents and isoform-resolved panels were not accessible here; a P-body pool is not the principal endolysosomal catalytic mechanism. The vocabulary mapping is consistent with this direct source. Supporting Evidence: |
| GO:0000932 P-body | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: C9orf72 is reported in processing bodies. Reason: The complete PMID:27037575 abstract explicitly reports localization of normal C9orf72 to P-bodies and stress-dependent redistribution. Retain this contextual compartment while recognizing that the original imaging, reagents and isoform-resolved panels were not accessible here; a P-body pool is not the principal endolysosomal catalytic mechanism. The vocabulary mapping is consistent with this direct source. Supporting Evidence: |
| GO:0001933 negative regulation of protein phosphorylation | IMP PMID:27723745 C9ORF72 interaction with cofilin modulates actin dynamics in... | KEEP AS NON CORE | Summary: C9orf72 restrains cofilin phosphorylation through a small-GTPase signaling pathway. Reason: PMID:27723745 reports increased cofilin phosphorylation after C9orf72 depletion and modulation of ARF6/RAC1–LIMK signaling. This supports a regulatory effect on phosphorylation, not intrinsic C9orf72 phosphatase or kinase activity. The complete abstract is available; detailed target-assay panels were not inspected. Supporting Evidence: |
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | UNDECIDED | Summary: Exchange activity of the C9orf72–SMCR8–WDR41 complex remains mechanistically contested. Reason: Positive primary GDP-release assays in PMID:27103069 and PMID:27617292 support the original complex-level claim and preserved contributes_to qualifier. In contrast, PMID:32848248 reports no detectable exchange by the human HEK293-purified heterotrimer on Rab1A, Rab5A, Rab7A, Rab8A or Rab39B, with a Rabex5/Rab5A positive control. This is an actual exchange-assay conflict, not an inference that a GAP cannot also be a GEF. Preparation, substrate and time-scale differences remain unresolved. The 2023 C9orf72-alone Rab39A experiment uses a different substrate/preparation and does not settle the earlier complex assays. Preserve UNDECIDED without discarding either positive evidence or curator judgment. The target in PAINT descendant evidence is legitimate, not circular; the ancestral node was not independently re-curated. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | UNDECIDED | Summary: Exchange activity of the C9orf72–SMCR8–WDR41 complex remains mechanistically contested. Reason: Positive primary GDP-release assays in PMID:27103069 and PMID:27617292 support the original complex-level claim and preserved contributes_to qualifier. In contrast, PMID:32848248 reports no detectable exchange by the human HEK293-purified heterotrimer on Rab1A, Rab5A, Rab7A, Rab8A or Rab39B, with a Rabex5/Rab5A positive control. This is an actual exchange-assay conflict, not an inference that a GAP cannot also be a GEF. Preparation, substrate and time-scale differences remain unresolved. The 2023 C9orf72-alone Rab39A experiment uses a different substrate/preparation and does not settle the earlier complex assays. Preserve UNDECIDED without discarding either positive evidence or curator judgment. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:27617292 A C9ORF72/SMCR8-containing complex regulates ULK1 and plays ... | UNDECIDED | Summary: Exchange activity of the C9orf72–SMCR8–WDR41 complex remains mechanistically contested. Reason: Positive primary GDP-release assays in PMID:27103069 and PMID:27617292 support the original complex-level claim and preserved contributes_to qualifier. In contrast, PMID:32848248 reports no detectable exchange by the human HEK293-purified heterotrimer on Rab1A, Rab5A, Rab7A, Rab8A or Rab39B, with a Rabex5/Rab5A positive control. This is an actual exchange-assay conflict, not an inference that a GAP cannot also be a GEF. Preparation, substrate and time-scale differences remain unresolved. The 2023 C9orf72-alone Rab39A experiment uses a different substrate/preparation and does not settle the earlier complex assays. Preserve UNDECIDED without discarding either positive evidence or curator judgment. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | ACCEPT | Summary: C9orf72 can promote guanine-nucleotide exchange on Rab39A. Reason: PMID:37821429 reports direct Rab39A binding, concentration-dependent Mant-GDP release by purified bacterially expressed C9orf72, and rescue of cellular autophagic-fusion defects by active Rab39A. Retain this substrate- and preparation-bounded activity. Its near-equimolar 7,200–14,000-second assays differ from the 1,400-second heterotrimer assays in PMID:32848248, which did not include Rab39A. The latter therefore does not directly disprove this C9orf72-alone result; neither experiment establishes identical exchange by every preparation or on every Rab. Supporting Evidence: PMID:37821429 C9orf72 strongly facilitated the release of Mant-GDP from Rab39A |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: C9orf72 can promote guanine-nucleotide exchange on Rab39A. Reason: PMID:37821429 reports direct Rab39A binding, concentration-dependent Mant-GDP release by purified bacterially expressed C9orf72, and rescue of cellular autophagic-fusion defects by active Rab39A. Retain this substrate- and preparation-bounded activity. Its near-equimolar 7,200–14,000-second assays differ from the 1,400-second heterotrimer assays in PMID:32848248, which did not include Rab39A. The latter therefore does not directly disprove this C9orf72-alone result; neither experiment establishes identical exchange by every preparation or on every Rab. The InterPro mapping is retained because target primary evidence corroborates it, not solely because of the DENN-domain name. |
| GO:0005096 GTPase activator activity | IMP PMID:32303654 Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as... | ACCEPT | Summary: C9orf72 contributes to GTPase activation by its SMCR8-containing complex. Reason: The complete PMID:32303654 abstract reports purified-complex GAP activity on Rab8A/Rab11A. Independently inspected PMID:32848248 and PMID:34145292 establish human complex ARF GAP activity with controls and a C9orf72 substrate-binding interface whose mutation impairs hydrolysis. SMCR8 supplies catalytic Arg147. Accept C9orf72 participation while preserving the source enables qualifier exactly; the authored core uses contributes_to_molecular_function to avoid an autonomous C9orf72 GAP active-site claim. Rab8A required substantially more complex than ARF1 in the 2021 preparation; physiological substrate selection remains open. Supporting Evidence: PMID:34145292 ARF1 sits in a 25 Å-wide concave pocket |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: Retain the curated EIF2B2 interaction from the human Stitch-seq/Y2H dataset. Reason: PMID:21516116 reports human ORFeome yeast two-hybrid interaction mapping with sequencing-based pair identification; its Methods describe bait/prey construction and autoactivator filtering. P49770 is EIF2B2 in the C9orf72 UniProt interaction record. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | UNDECIDED | Summary: Retain uncertainty about the reported C9orf72–hnRNPA1 interaction because the endogenous assay relies on a subsequently questioned C9orf72 antibody. Reason: PMID:24549040 reports hnRNPA1 coassociation after endogenous immunoprecipitation and mass-spectrometry screening. Its unique Results describe reverse hnRNP-antibody precipitation, while the Figure 7 caption describes anti-C9orf72 precipitation; both interpretations rely on the sc-138763 C9orf72 reagent for capture or detection. The mass-spectrometry discovery also used that reagent. PMID:30075745 explicitly includes sc-138763 among tested commercial antibodies and reports deficient specificity against knockout mouse controls. This does not demonstrate that the human SH-SY5Y interaction is false, but it leaves the target identity of this particular antibody-dependent edge unresolved. The inspected GFP-C9orf72 experiment assesses stress-granule induction, not an antibody-independent tagged-protein binding validation. No independent reagent-resolved hnRNP binding experiment was identified in this bounded reading. Preserve the original curated source and partner rather than remove the annotation or call it verified. |
| GO:0005515 protein binding | IPI PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | UNDECIDED | Summary: Retain uncertainty about the reported C9orf72–hnRNPA2/B1 interaction because the endogenous assay relies on a subsequently questioned C9orf72 antibody. Reason: PMID:24549040 reports hnRNPA2/B1 coassociation after endogenous immunoprecipitation and mass-spectrometry screening. Its unique Results describe reverse hnRNP-antibody precipitation, while the Figure 7 caption describes anti-C9orf72 precipitation; both interpretations rely on the sc-138763 C9orf72 reagent for capture or detection. The mass-spectrometry discovery also used that reagent. PMID:30075745 explicitly includes sc-138763 among tested commercial antibodies and reports deficient specificity against knockout mouse controls. This does not demonstrate that the human SH-SY5Y interaction is false, but it leaves the target identity of this particular antibody-dependent edge unresolved. The inspected GFP-C9orf72 experiment assesses stress-granule induction, not an antibody-independent tagged-protein binding validation. No independent reagent-resolved hnRNP binding experiment was identified in this bounded reading. Preserve the original curated source and partner rather than remove the annotation or call it verified. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Refine the curated CRX interaction to DNA-binding transcription factor binding. Reason: PMID:25416956 provides the human binary Y2H interaction framework; the exact O43186 edge is also present in the curated C9orf72 UniProt interaction record. Official human gene records identify CRX as a sequence-specific DNA-binding transcription factor, making GO:0140297 more informative than generic protein binding. The target table has not been independently inspected, so this refinement retains the original curator-supported edge and does not assert that C9orf72 itself binds DNA, regulates a particular promoter, or acts as a transcriptional cofactor. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Refine the curated c-Rel interaction to DNA-binding transcription factor binding. Reason: PMID:25416956 provides the human binary Y2H interaction framework; the exact Q04864 edge is also present in the curated C9orf72 UniProt interaction record. Official human gene records identify c-Rel as a sequence-specific DNA-binding transcription factor, making GO:0140297 more informative than generic protein binding. The target table has not been independently inspected, so this refinement retains the original curator-supported edge and does not assert that C9orf72 itself binds DNA, regulates a particular promoter, or acts as a transcriptional cofactor. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curated interaction with NMI/Q13287. Reason: PMID:25416956 used a systematic human ORFeome binary Y2H map with dataset-level orthogonal validation. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. The literal supporting accession is preserved; distinct EIF2B2 source accessions are not collapsed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curated interaction with the source EIF2B2 accession Q53XC2. Reason: PMID:25416956 used a systematic human ORFeome binary Y2H map with dataset-level orthogonal validation. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. The literal supporting accession is preserved; distinct EIF2B2 source accessions are not collapsed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Retain the curated interaction with the source EIF2B2 accession Q9BPX4. Reason: PMID:25416956 used a systematic human ORFeome binary Y2H map with dataset-level orthogonal validation. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. The literal supporting accession is preserved; distinct EIF2B2 source accessions are not collapsed. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | MODIFY | Summary: Refine the HSC70/HSPA8 interaction to Hsp70 protein binding. Reason: The canonical PMID:27103069 cache is abstract-only; the authenticated fuller normal-fetch variant was read as supplemental evidence. Its Results report human codon-optimized C9ORF72 expressed in mouse Neuro-2A cells, tandem affinity purification and immunoblot confirmation of HSC70 association, followed by co-IP evidence for C9ORF72/SMCR8 binding to HSC70. The paper identifies HSC70 as HSPA8, matching the source P11142 class. GO:0030544 captures this partner specificity. Whether C9orf72 is a chaperone client or regulator remains unresolved; neither chaperone catalysis nor direct BAG3 binding is inferred. No species-specific purified-pair affinity or canonical full-text-cache claim is made. Proposed replacements: Hsp70 protein binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | KEEP AS NON CORE | Summary: Retain the SMCR8 interaction underlying the C9orf72 complex. Reason: PMID:27103069 supplemental full-text Results describe co-IP with tagged human C9ORF72 and SMCR8 and recovery of a recombinant complex from insect-cell expression. The shorter C9orf72 form failed this association in the reported assay, so binding is not generalized across products. Canonical PMID:32303654 independently supports a human C9ORF72–SMCR8 interface. Generic binding is retained as assembly support without becoming an additional generic-binding core or conferring every SMCR8 catalytic property. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | KEEP AS NON CORE | Summary: Retain the BFG-Y2H SMCR8 interaction with independent complex evidence. Reason: PMID:27107012 provides the Barcode Fusion Genetics yeast two-hybrid framework. The exact Q8TEV9/SMCR8 edge is curator-supported and independently substantiated by endogenous co-IP in PMID:27559131 and the human complex structure in PMID:32303654. The individual BFG target table has not been re-inspected. The interaction is retained without asserting that the screen itself established GAP or GEF activity. |
| GO:0005515 protein binding | IPI PMID:27559131 C9orf72 binds SMCR8, localizes to lysosomes, and regulates m... | KEEP AS NON CORE | Summary: Retain the strong endogenous C9orf72–SMCR8 complex interaction. Reason: PMID:27559131 used genome-edited HEK293FT cells expressing tagged C9orf72 from its endogenous locus and recovered endogenous SMCR8, but not FLCN or FNIP1. Tagged coexpression, near-stoichiometric recovery and resistance to high salt/detergent further support the complex. The binding annotation is correct but is assembly evidence rather than a separate informative core activity. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28195531 Multiplex image-based autophagy RNAi screening identifies SM... | KEEP AS NON CORE | Summary: Retain the SMCR8 association validated in the autophagy-complex study. Reason: The existing canonical full XML for PMID:28195531 reports SMCR8 IP-MS, tagged-protein and endogenous coassociation analyses, and a stable C9ORF72–SMCR8–WDR41 complex that can join the ULK1 assembly. The paper title foregrounds SMCR8 but the actual C9orf72 association was examined; no wrong-gene objection is warranted. C9orf72 is not assigned ULK1 kinase activity or SMCR8 transcriptional effects by this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with POP7/O75817. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with COIL/P38432. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with EIF2B2/P49770. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with SYN3/Q17R54. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with TRIM74 isoform Q86UV6-2. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. The -2 suffix belongs to the interacting TRIM74 product and remains unchanged; it is not a C9orf72 isoform annotation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the HuRI SMCR8 edge with independently established complex support. Reason: PMID:32296183 supplies the human binary-screen framework and the exact Q8TEV9 edge agrees with the curated UniProt interaction record. PMID:27559131 and PMID:32303654 independently demonstrate C9orf72–SMCR8 association. The individual HuRI pair output was not inspected and no additional source-specific validation is invented. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with VRTN/Q9H8Y1. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the curated HuRI interaction with HMG20A/Q9NP66. Reason: PMID:32296183 describes an all-by-all human binary-interaction map generated using multiple Y2H configurations. The human binary-interaction assay framework is accessible, and the exact partner is independently retained in the curated UniProt interaction record. The individual source table or clone-level result has not been re-inspected; retention defers to that source-specific curation, not a claim that every reported edge was independently replicated. This supports a contextual physical interaction without transferring the partner's biological role to C9orf72. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32303654 Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as... | KEEP AS NON CORE | Summary: Retain association with the SMCR8–WDR41 complex, preserving both source partners. Reason: PMID:32303654 reports the human cryo-EM complex and explicitly places SMCR8 between C9ORF72 and WDR41, without a direct C9ORF72–WDR41 contact. The literal Q8TEV9 and Q9HAD4 partner list is preserved. This row is retained as complex physical association/direct SMCR8 contact, not as two proven independent binary interfaces or catalytic activity on WDR41. The canonical abstract is sufficient for this structural boundary; full Methods were not read. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Retain BioPlex SMCR8 coassociation with independent direct-complex evidence. Reason: PMID:33961781 supplies affinity-purification mass-spectrometry maps from human 293T and HCT116 cells. Selected Methods in the authenticated fuller normal variant were read; the individual C9orf72–SMCR8 network row was not independently inspected. The source edge matches curated UniProt and independent PMID:27559131/PMID:32303654 complex evidence, supporting non-core retention without claiming AP-MS alone proves a direct interface. |
| GO:0005515 protein binding | IPI PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | MODIFY | Summary: Refine direct RAB39A binding to small GTPase binding. Reason: PMID:37821429 Results and Figure 6 describe C9orf72 association with both Rab39 proteins in transfected human 293T cells and direct pull-down of purified Myc-C9orf72 by GST-tagged Rab39 proteins; GDP-loaded mutants increase association. Official UniProt identifies Q14964 as RAB39A. GO:0031267 specifically captures binding to a small monomeric GTPase; the current official AmiGO record includes the older Rab-binding identifier GO:0017137 as an alternate ID. Binding is supported independently of whether a given preparation has GEF activity; this refinement does not transfer RAB39A GTP hydrolysis to C9orf72. Proposed replacements: small GTPase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | MODIFY | Summary: Refine direct RAB39B binding to small GTPase binding. Reason: PMID:37821429 Results and Figure 6 describe C9orf72 association with both Rab39 proteins in transfected human 293T cells and direct pull-down of purified Myc-C9orf72 by GST-tagged Rab39 proteins; GDP-loaded mutants increase association. Official UniProt identifies Q96DA2 as RAB39B. GO:0031267 specifically captures binding to a small monomeric GTPase; the current official AmiGO record includes the older Rab-binding identifier GO:0017137 as an alternate ID. Binding is supported independently of whether a given preparation has GEF activity; this refinement does not transfer RAB39B GTP hydrolysis to C9orf72. Proposed replacements: small GTPase binding Supporting Evidence: |
| GO:0005576 extracellular region | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | UNDECIDED | Summary: An extracellular C9orf72 pool is not securely established by the inspected evidence. Reason: PMID:24549040 reports conditioned-medium/CSF immunoreactivity, but the commercial sc-138763 reagent used in that study was subsequently included among poorly specific reagents tested with knockout controls in PMID:30075745. The electronic mapping does not independently resolve that source limitation. Neither absence of a conventional secretion signal nor antibody uncertainty proves that secretion is impossible; retain uncertainty pending specific endogenous detection. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | UNDECIDED | Summary: An extracellular C9orf72 pool is not securely established by the inspected evidence. Reason: PMID:24549040 reports conditioned-medium/CSF immunoreactivity, but the commercial sc-138763 reagent used in that study was subsequently included among poorly specific reagents tested with knockout controls in PMID:30075745. The electronic mapping does not independently resolve that source limitation. Neither absence of a conventional secretion signal nor antibody uncertainty proves that secretion is impossible; retain uncertainty pending specific endogenous detection. |
| GO:0005634 nucleus | EXP PMID:21944779 A hexanucleotide repeat expansion in C9ORF72 is the cause of... | UNDECIDED | Summary: The early predominantly nuclear immunostaining requires specificity confirmation. Reason: PMID:21944779 itself calls the Santa Cruz antibody largely uncharacterized and notes an effect of control siRNA. Later knockout-controlled work supports predominantly cytoplasmic/presynaptic C9orf72. This is a concrete reagent limitation, not rejection of an experimental annotation from its disease-focused title; it does not prove that every nuclear or short-isoform pool is absent. |
| GO:0005634 nucleus | EXP PMID:26174152 Isoform-specific antibodies reveal distinct subcellular loca... | UNDECIDED | Summary: The reported short-isoform-associated nuclear localization remains unresolved. Reason: PMID:26174152 uses custom isoform-specific antibodies and reports different long- and short-product distributions in human tissue. Its complete abstract is available, but the original specificity controls and images were not inspected. The 2018 commercial-antibody tests do not establish that these custom reagents were tested, so a universal negative nuclear conclusion would be unwarranted. |
| GO:0005634 nucleus | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | UNDECIDED | Summary: Nuclear immunoreactivity from the older commercial reagent is uncertain. Reason: The sc-138763 endogenous staining in PMID:24549040 is affected by the later knockout-specificity concern in PMID:30075745. Tagged-protein nuclear entry in separate experiments does not validate the older endogenous signal, and the 2017 image/legend correction is not an antibody-validation experiment. |
| GO:0005634 nucleus | IDA PMID:27037575 C9ORF72 Regulates Stress Granule Formation and Its Deficienc... | UNDECIDED | Summary: A constitutive native nuclear pool is not resolved by the available source evidence. Reason: The accessible PMID:27037575 abstract supports P-bodies and stress granules, while the exact nuclear imaging and reagent controls were not accessible. Mouse/vocabulary propagation and nuclear signal from tagged overexpression do not independently establish the corresponding native pool. In light of the source-specific antibody uncertainties, preserve this assertion as undecided rather than declaring it false. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | UNDECIDED | Summary: A constitutive native nuclear pool is not resolved by the available source evidence. Reason: The accessible PMID:27037575 abstract supports P-bodies and stress granules, while the exact nuclear imaging and reagent controls were not accessible. Mouse/vocabulary propagation and nuclear signal from tagged overexpression do not independently establish the corresponding native pool. In light of the source-specific antibody uncertainties, preserve this assertion as undecided rather than declaring it false. |
| GO:0005737 cytoplasm | EXP PMID:21944778 Expanded GGGGCC hexanucleotide repeat in noncoding region of... | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005737 cytoplasm | EXP PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005737 cytoplasm | IDA PMID:27037575 C9ORF72 Regulates Stress Granule Formation and Its Deficienc... | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005737 cytoplasm | IDA PMID:27193190 The ALS/FTLD associated protein C9orf72 associates with SMCR... | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005764 lysosome | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | ACCEPT | Summary: C9orf72 associates with lysosomes in a nutrient-dependent manner. Reason: Endogenous 2xHA-tagged C9orf72 in PMID:27559131 moves from diffuse cytoplasm to LAMP1-positive structures during amino-acid starvation and redistributes after refeeding. Independent PMID:30075745 detection supports partial lysosomal association. This corroborates the compartment even where the original older antibody was uncertain; association does not imply lysosomal lumenal cargo or membrane-spanning topology. |
| GO:0005764 lysosome | IDA PMID:27559131 C9orf72 binds SMCR8, localizes to lysosomes, and regulates m... | ACCEPT | Summary: C9orf72 associates with lysosomes in a nutrient-dependent manner. Reason: Endogenous 2xHA-tagged C9orf72 in PMID:27559131 moves from diffuse cytoplasm to LAMP1-positive structures during amino-acid starvation and redistributes after refeeding. Independent PMID:30075745 detection supports partial lysosomal association. This corroborates the compartment even where the original older antibody was uncertain; association does not imply lysosomal lumenal cargo or membrane-spanning topology. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: C9orf72 associates with lysosomes in a nutrient-dependent manner. Reason: Endogenous 2xHA-tagged C9orf72 in PMID:27559131 moves from diffuse cytoplasm to LAMP1-positive structures during amino-acid starvation and redistributes after refeeding. Independent PMID:30075745 detection supports partial lysosomal association. This corroborates the compartment even where the original older antibody was uncertain; association does not imply lysosomal lumenal cargo or membrane-spanning topology. |
| GO:0005768 endosome | IBA GO_REF:0000033 | UNDECIDED | Summary: The specific endosomal localization remains unresolved after a concrete reagent-specific concern. Reason: PMID:24549040 reports endosomal labeling using sc-138763, which was among the commercial reagents challenged by later mouse knockout testing in PMID:30075745. Independent lysosomal/autolysosomal localization, Rab binding and trafficking phenotypes support endolysosomal biology but do not directly resolve a distinct endosomal pool. Preserve the experimental, PAINT and vocabulary assertions as UNDECIDED rather than treating these adjacent observations as a location assay or declaring the original human pool disproved. Target-as-descendant PAINT evidence is legitimate, not circular, and the tree was not independently re-curated. |
| GO:0005768 endosome | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | UNDECIDED | Summary: The specific endosomal localization remains unresolved after a concrete reagent-specific concern. Reason: PMID:24549040 reports endosomal labeling using sc-138763, which was among the commercial reagents challenged by later mouse knockout testing in PMID:30075745. Independent lysosomal/autolysosomal localization, Rab binding and trafficking phenotypes support endolysosomal biology but do not directly resolve a distinct endosomal pool. Preserve the experimental, PAINT and vocabulary assertions as UNDECIDED rather than treating these adjacent observations as a location assay or declaring the original human pool disproved. Target-as-descendant PAINT evidence is legitimate, not circular, and the tree was not independently re-curated. |
| GO:0005768 endosome | IEA GO_REF:0000044 | UNDECIDED | Summary: The specific endosomal localization remains unresolved after a concrete reagent-specific concern. Reason: PMID:24549040 reports endosomal labeling using sc-138763, which was among the commercial reagents challenged by later mouse knockout testing in PMID:30075745. Independent lysosomal/autolysosomal localization, Rab binding and trafficking phenotypes support endolysosomal biology but do not directly resolve a distinct endosomal pool. Preserve the experimental, PAINT and vocabulary assertions as UNDECIDED rather than treating these adjacent observations as a location assay or declaring the original human pool disproved. Target-as-descendant PAINT evidence is legitimate, not circular, and the tree was not independently re-curated. |
| GO:0005776 autophagosome | IBA GO_REF:0000033 | ACCEPT | Summary: C9orf72 associates with the autophagic membrane pathway. Reason: Autophagy-dependent localization and Rab39A–HOPS recruitment in PMID:37821429, together with ULK1-complex trafficking in PMID:27334615, support action at autophagic structures. This independently corroborates the curated autophagosome assertion despite limitations of the original 2014 antibody. It does not make C9orf72 a constitutive membrane-spanning or lumenal autophagosome constituent. |
| GO:0005776 autophagosome | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | ACCEPT | Summary: C9orf72 associates with the autophagic membrane pathway. Reason: Autophagy-dependent localization and Rab39A–HOPS recruitment in PMID:37821429, together with ULK1-complex trafficking in PMID:27334615, support action at autophagic structures. This independently corroborates the curated autophagosome assertion despite limitations of the original 2014 antibody. It does not make C9orf72 a constitutive membrane-spanning or lumenal autophagosome constituent. |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | ACCEPT | Summary: C9orf72 associates with the autophagic membrane pathway. Reason: Autophagy-dependent localization and Rab39A–HOPS recruitment in PMID:37821429, together with ULK1-complex trafficking in PMID:27334615, support action at autophagic structures. This independently corroborates the curated autophagosome assertion despite limitations of the original 2014 antibody. It does not make C9orf72 a constitutive membrane-spanning or lumenal autophagosome constituent. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0005829 cytosol | IDA PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | ACCEPT | Summary: C9orf72 has a substantial cytoplasmic/cytosolic pool. Reason: This broad compartment is independently supported by tagged endogenous C9orf72 in PMID:27559131, knockout-validated antibody work in PMID:30075745, and the human-cell localization experiments in PMID:37821429. Earlier antibody results and the HPA/vocabulary mappings are retained by claim-level corroboration; the original HPA image was not independently inspected. Soluble cytosol is distinct from an integral membrane or organelle-lumen assignment. |
| GO:0006897 endocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: C9orf72 contributes to endocytic trafficking in the tested cellular context. Reason: PMID:24549040 reports siRNA-dependent defects in endocytic cargo trafficking. The ddx309 correction replaces a Fig. 5E internalized-TrkB image; authors state quantification used the correct blot and conclusions were unchanged. Antibody-localization caveats do not automatically invalidate the separate perturbation assays. Retain the broad pathway role, without generalizing to every cargo or equating necessity with a universal endocytic catalyst. Supporting Evidence: |
| GO:0006897 endocytosis | IMP PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | KEEP AS NON CORE | Summary: C9orf72 contributes to endocytic trafficking in the tested cellular context. Reason: PMID:24549040 reports siRNA-dependent defects in endocytic cargo trafficking. The ddx309 correction replaces a Fig. 5E internalized-TrkB image; authors state quantification used the correct blot and conclusions were unchanged. Antibody-localization caveats do not automatically invalidate the separate perturbation assays. Retain the broad pathway role, without generalizing to every cargo or equating necessity with a universal endocytic catalyst. Supporting Evidence: |
| GO:0006914 autophagy | IMP PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | ACCEPT | Summary: C9orf72 participates in autophagy through small-GTPase regulation and trafficking machinery. Reason: The broad autophagy annotation is independently supported by direct biochemical and cellular mechanisms in PMID:27334615 and PMID:37821429. These establish molecular work in initiation-complex trafficking and Rab39A activation, not only a loss-of-function phenotype. The original 2014 source remains identified and its correction and antibody limits are recorded separately. |
| GO:0010494 cytoplasmic stress granule | IDA PMID:27037575 C9ORF72 Regulates Stress Granule Formation and Its Deficienc... | KEEP AS NON CORE | Summary: C9orf72 is recruited to cytoplasmic stress granules. Reason: The complete PMID:27037575 abstract directly reports stress-induced recruitment of normal C9orf72 and distinguishes a long-isoform contribution to granule assembly. Preserve the contextual localization; pathogenic repeat RNA and dipeptide-repeat products are different molecular entities and are not used to assign this native-protein activity. Supporting Evidence: |
| GO:0010494 cytoplasmic stress granule | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: C9orf72 is recruited to cytoplasmic stress granules. Reason: The complete PMID:27037575 abstract directly reports stress-induced recruitment of normal C9orf72 and distinguishes a long-isoform contribution to granule assembly. Preserve the contextual localization; pathogenic repeat RNA and dipeptide-repeat products are different molecular entities and are not used to assign this native-protein activity. Supporting Evidence: |
| GO:0010506 regulation of autophagy | IBA GO_REF:0000033 | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. |
| GO:0010506 regulation of autophagy | IEA GO_REF:0000107 | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. |
| GO:0010506 regulation of autophagy | IMP PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. |
| GO:0016239 positive regulation of macroautophagy | IGI PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:27334615 The C9orf72 protein interacts with Rab1a and the ULK1 comple... | ACCEPT | Summary: C9orf72 regulates macroautophagy. Reason: Primary C9orf72 depletion/rescue, Rab39B epistasis and ULK1-complex trafficking experiments support a native-protein regulatory role. PMID:27103069 has an abstract-only canonical cache, with detailed Results inspected in the authenticated fuller variant; PMID:27334615 supplies accessible human-cell and rat-neuron experiments with human rescue. The Rab39B-QL rescue supports regulation without uniquely proving the disputed catalytic direction of the whole complex. Mouse/PAINT transfer is independently consistent with target evidence and is not rejected for self-descendant support. Supporting Evidence: PMID:27334615 C9orf72 binds to Rab1a and behaves as a Rab1a effector |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0030425 dendrite | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0030426 growth cone | IEA GO_REF:0000044 | UNDECIDED | Summary: The precise growth-cone or main-axon assignment needs the original localization evidence. Reason: PMID:27723745 directly supports a native C9orf72–small-GTPase–cofilin pathway in motor neurons, but its normal cache is abstract-only and the exact compartment-specific images/construct controls were not inspected. Broad neuronal localization does not alone resolve these finer assignments. This is an access limit, not evidence that the curated localization is wrong. Supporting Evidence: |
| GO:0031267 small GTPase binding | IDA PMID:24549040 C9ORF72, implicated in amytrophic lateral sclerosis and fron... | ACCEPT | Summary: C9orf72 directly recognizes small Rab GTPases. Reason: Independent binding experiments in PMID:27334615 demonstrate preferential association with active Rab1A, and PMID:37821429 reports direct interaction with Rab39A/Rab39B. These support the specific binding function beyond the older antibody-dependent source and the ortholog mapping. Binding to one Rab as an effector does not establish exchange activity on that same Rab. |
| GO:0031267 small GTPase binding | IEA GO_REF:0000107 | ACCEPT | Summary: C9orf72 directly recognizes small Rab GTPases. Reason: Independent binding experiments in PMID:27334615 demonstrate preferential association with active Rab1A, and PMID:37821429 reports direct interaction with Rab39A/Rab39B. These support the specific binding function beyond the older antibody-dependent source and the ortholog mapping. Binding to one Rab as an effector does not establish exchange activity on that same Rab. |
| GO:0031965 nuclear membrane | EXP PMID:26174152 Isoform-specific antibodies reveal distinct subcellular loca... | UNDECIDED | Summary: The short-product nuclear membrane pool remains unresolved. Reason: The complete PMID:26174152 abstract attributes nuclear-membrane labeling to a custom C9-S antibody. Original validation and images are unavailable here, and later testing of commercial antibodies is not a direct test of this reagent. Preserve the source assertion and products without treating transcript labels or a mouse long-isoform negative result as proof against the human short form. |
| GO:0031965 nuclear membrane | IEA GO_REF:0000044 | UNDECIDED | Summary: The short-product nuclear membrane pool remains unresolved. Reason: The complete PMID:26174152 abstract attributes nuclear-membrane labeling to a custom C9-S antibody. Original validation and images are unavailable here, and later testing of commercial antibodies is not a direct test of this reagent. Preserve the source assertion and products without treating transcript labels or a mouse long-isoform negative result as proof against the human short form. |
| GO:0032045 guanyl-nucleotide exchange factor complex | IDA PMID:27103069 Loss of C9ORF72 impairs autophagy and synergizes with polyQ ... | UNDECIDED | Summary: The physical C9orf72–SMCR8–WDR41 complex is established, but its classification as a GEF complex is contested. Reason: The physical assembly is established by co-purification and structural work. GO:0032045 additionally classifies it by exchange activity: the original positive complex assays in PMID:27103069 conflict with negative exchange assays in PMID:32848248. GAP activity and physical association alone do not resolve this functional complex class. Retain the exact source object as UNDECIDED rather than inventing a replacement that erases genuine assay differences. |
| GO:0032880 regulation of protein localization | IEA GO_REF:0000107 | ACCEPT | Summary: C9orf72 regulates the localization of trafficking machinery. Reason: The broad ortholog-derived term is independently supported by human C9orf72-dependent recruitment of the ULK1 initiation machinery in PMID:27334615 and Rab39A/HOPS localization in PMID:37821429. This does not require claiming that every mouse target protein or transport route was independently assayed in human cells. |
| GO:0034063 cytoplasmic stress granule assembly | IMP PMID:27037575 C9ORF72 Regulates Stress Granule Formation and Its Deficienc... | KEEP AS NON CORE | Summary: The long native C9orf72 product contributes to stress-granule assembly. Reason: The complete PMID:27037575 abstract reports gain- and loss-of-function tests of normal C9orf72 and loss of granule formation after depletion. Retain this contextual process without assigning an unmeasured condensate-forming physical activity. Effects of expanded repeat RNA are separately described and not transferred to the normal protein. Supporting Evidence: PMID:27037575 long isoform of C9ORF72 protein regulates SG assembly. |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0043204 perikaryon | EXP PMID:26174152 Isoform-specific antibodies reveal distinct subcellular loca... | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0043204 perikaryon | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0043204 perikaryon | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: C9orf72 is present in neuronal processes and cell bodies. Reason: The human isoform-localization abstract PMID:26174152 and validated antibody study PMID:30075745 support neuronal cytoplasmic/process pools. Preserve the broader mouse/UniProt/PAINT assertions with their original provenance rather than recasting them as a new human experiment. Fine short-isoform nuclear membrane claims are assessed separately; neuronal localization is contextual rather than a separate molecular mechanism. |
| GO:0044295 axonal growth cone | IDA PMID:27723745 C9ORF72 interaction with cofilin modulates actin dynamics in... | UNDECIDED | Summary: The precise growth-cone or main-axon assignment needs the original localization evidence. Reason: PMID:27723745 directly supports a native C9orf72–small-GTPase–cofilin pathway in motor neurons, but its normal cache is abstract-only and the exact compartment-specific images/construct controls were not inspected. Broad neuronal localization does not alone resolve these finer assignments. This is an access limit, not evidence that the curated localization is wrong. Supporting Evidence: |
| GO:0044304 main axon | IDA PMID:27723745 C9ORF72 interaction with cofilin modulates actin dynamics in... | UNDECIDED | Summary: The precise growth-cone or main-axon assignment needs the original localization evidence. Reason: PMID:27723745 directly supports a native C9orf72–small-GTPase–cofilin pathway in motor neurons, but its normal cache is abstract-only and the exact compartment-specific images/construct controls were not inspected. Broad neuronal localization does not alone resolve these finer assignments. This is an access limit, not evidence that the curated localization is wrong. Supporting Evidence: |
| GO:0044754 autolysosome | EXP PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | ACCEPT | Summary: C9orf72 associates with autolysosomes during induced autophagy. Reason: PMID:37821429 reports C9orf72 redistribution from cytosol to autolysosomal structures and a Rab39A-dependent fusion mechanism. Preserve the experimentally and vocabulary-derived compartment without asserting a lumenal or integral membrane topology. Supporting Evidence: |
| GO:0044754 autolysosome | IEA GO_REF:0000044 | ACCEPT | Summary: C9orf72 associates with autolysosomes during induced autophagy. Reason: PMID:37821429 reports C9orf72 redistribution from cytosol to autolysosomal structures and a Rab39A-dependent fusion mechanism. Preserve the experimentally and vocabulary-derived compartment without asserting a lumenal or integral membrane topology. Supporting Evidence: |
| GO:0048675 axon extension | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: C9orf72 regulates axonal actin dynamics and neuronal outgrowth. Reason: PMID:27723745 reports C9orf72-dependent ARF6/RAC1–LIMK/cofilin regulation and rescue by dominant-negative ARF6. This supports the curated motor-neuron actin/outgrowth role, bounded by the complete accessible abstract and original curator interpretation for finer assays. It does not imply that C9orf72 itself phosphorylates cofilin or polymerizes actin. The ortholog and PAINT rows are consistent with this evidence, not assessed by donor count. Supporting Evidence: |
| GO:0048675 axon extension | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: C9orf72 regulates axonal actin dynamics and neuronal outgrowth. Reason: PMID:27723745 reports C9orf72-dependent ARF6/RAC1–LIMK/cofilin regulation and rescue by dominant-negative ARF6. This supports the curated motor-neuron actin/outgrowth role, bounded by the complete accessible abstract and original curator interpretation for finer assays. It does not imply that C9orf72 itself phosphorylates cofilin or polymerizes actin. The ortholog and PAINT rows are consistent with this evidence, not assessed by donor count. Supporting Evidence: |
| GO:0048675 axon extension | IMP PMID:27723745 C9ORF72 interaction with cofilin modulates actin dynamics in... | KEEP AS NON CORE | Summary: C9orf72 regulates axonal actin dynamics and neuronal outgrowth. Reason: PMID:27723745 reports C9orf72-dependent ARF6/RAC1–LIMK/cofilin regulation and rescue by dominant-negative ARF6. This supports the curated motor-neuron actin/outgrowth role, bounded by the complete accessible abstract and original curator interpretation for finer assays. It does not imply that C9orf72 itself phosphorylates cofilin or polymerizes actin. The ortholog and PAINT rows are consistent with this evidence, not assessed by donor count. Supporting Evidence: |
| GO:0061909 autophagosome-lysosome fusion | IMP PMID:37821429 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediate... | ACCEPT | Summary: C9orf72 promotes autophagosome–lysosome fusion through Rab39A activation. Reason: PMID:37821429 combines nucleotide-exchange assays, recruitment of HOPS and cellular C9orf72 loss/rescue experiments. The gene product does molecular work upstream of tether assembly; it is not merely consumed by the fusion process. C9orf72 is not assigned the intrinsic tethering or SNARE fusogenic activity performed by downstream machinery. Supporting Evidence: |
| GO:0098686 hippocampal mossy fiber to CA3 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-derived excitatory-synapse/vesicle-cycle role is retained with explicit species limits. Reason: The curated Q6DFW0 transfer is consistent with knockout-controlled mouse presynaptic localization in PMID:30075745 and independently inspected official primary summaries of synapsin-dependent excitatory-synapse function. These latter donor summaries are documented with URLs in the notes, not represented as newly cached references or a human target assay. Retain the conserved contextual role without claiming that the human hippocampal subregion and every vesicle-cycle experiment were directly examined. Supporting Evidence: |
| GO:0098693 regulation of synaptic vesicle cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-derived excitatory-synapse/vesicle-cycle role is retained with explicit species limits. Reason: The curated Q6DFW0 transfer is consistent with knockout-controlled mouse presynaptic localization in PMID:30075745 and independently inspected official primary summaries of synapsin-dependent excitatory-synapse function. These latter donor summaries are documented with URLs in the notes, not represented as newly cached references or a human target assay. Retain the conserved contextual role without claiming that the human hippocampal subregion and every vesicle-cycle experiment were directly examined. Supporting Evidence: |
| GO:0098793 presynapse | IEA GO_REF:0000120 | ACCEPT | Summary: C9orf72 is enriched in the soluble presynaptic compartment. Reason: PMID:30075745 uses newly developed antibodies, mouse knockout controls, brain fractionation and human iPSC-derived motor-neuron staining. Synaptosomal C9orf72 is enriched in soluble cytosolic fractions rather than establishing vesicle lumenal or transmembrane residence. The curated human assertion and propagation are retained with explicit mouse-versus-human assay boundaries; expression evidence is not converted into an independent catalytic assay. Supporting Evidence: |
| GO:0098793 presynapse | ISS GO_REF:0000024 | ACCEPT | Summary: C9orf72 is enriched in the soluble presynaptic compartment. Reason: PMID:30075745 uses newly developed antibodies, mouse knockout controls, brain fractionation and human iPSC-derived motor-neuron staining. Synaptosomal C9orf72 is enriched in soluble cytosolic fractions rather than establishing vesicle lumenal or transmembrane residence. The curated human assertion and propagation are retained with explicit mouse-versus-human assay boundaries; expression evidence is not converted into an independent catalytic assay. Supporting Evidence: |
| GO:0098794 postsynapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Postsynaptic localization is retained as a context-dependent ortholog-derived compartment. Reason: The mouse Q6DFW0 record and independently inspected primary synopsis of postsynaptic work support this conserved compartment, while PMID:30075745 preferentially detects a soluble presynaptic pool and little protein in its isolated postsynaptic-density fraction. Different preparations do not prove universal absence from all postsynaptic sites. Retention defers to the curated donor evidence and does not claim that a human postsynaptic target assay or the entire donor paper was inspected. Supporting Evidence: |
| GO:0098794 postsynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Postsynaptic localization is retained as a context-dependent ortholog-derived compartment. Reason: The mouse Q6DFW0 record and independently inspected primary synopsis of postsynaptic work support this conserved compartment, while PMID:30075745 preferentially detects a soluble presynaptic pool and little protein in its isolated postsynaptic-density fraction. Different preparations do not prove universal absence from all postsynaptic sites. Retention defers to the curated donor evidence and does not claim that a human postsynaptic target assay or the entire donor paper was inspected. Supporting Evidence: |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-derived excitatory-synapse/vesicle-cycle role is retained with explicit species limits. Reason: The curated Q6DFW0 transfer is consistent with knockout-controlled mouse presynaptic localization in PMID:30075745 and independently inspected official primary summaries of synapsin-dependent excitatory-synapse function. These latter donor summaries are documented with URLs in the notes, not represented as newly cached references or a human target assay. Retain the conserved contextual role without claiming that the human hippocampal subregion and every vesicle-cycle experiment were directly examined. Supporting Evidence: |
| GO:0099523 presynaptic cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: C9orf72 is enriched in the soluble presynaptic compartment. Reason: PMID:30075745 uses newly developed antibodies, mouse knockout controls, brain fractionation and human iPSC-derived motor-neuron staining. Synaptosomal C9orf72 is enriched in soluble cytosolic fractions rather than establishing vesicle lumenal or transmembrane residence. The curated human assertion and propagation are retained with explicit mouse-versus-human assay boundaries; expression evidence is not converted into an independent catalytic assay. Supporting Evidence: |
| GO:0099523 presynaptic cytosol | IDA PMID:30075745 Novel antibodies reveal presynaptic localization of C9orf72 ... | ACCEPT | Summary: C9orf72 is enriched in the soluble presynaptic compartment. Reason: PMID:30075745 uses newly developed antibodies, mouse knockout controls, brain fractionation and human iPSC-derived motor-neuron staining. Synaptosomal C9orf72 is enriched in soluble cytosolic fractions rather than establishing vesicle lumenal or transmembrane residence. The curated human assertion and propagation are retained with explicit mouse-versus-human assay boundaries; expression evidence is not converted into an independent catalytic assay. Supporting Evidence: |
| GO:0099523 presynaptic cytosol | IEP PMID:30075745 Novel antibodies reveal presynaptic localization of C9orf72 ... | ACCEPT | Summary: C9orf72 is enriched in the soluble presynaptic compartment. Reason: PMID:30075745 uses newly developed antibodies, mouse knockout controls, brain fractionation and human iPSC-derived motor-neuron staining. Synaptosomal C9orf72 is enriched in soluble cytosolic fractions rather than establishing vesicle lumenal or transmembrane residence. The curated human assertion and propagation are retained with explicit mouse-versus-human assay boundaries; expression evidence is not converted into an independent catalytic assay. Supporting Evidence: |
| GO:0110053 regulation of actin filament organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: C9orf72 regulates axonal actin dynamics and neuronal outgrowth. Reason: PMID:27723745 reports C9orf72-dependent ARF6/RAC1–LIMK/cofilin regulation and rescue by dominant-negative ARF6. This supports the curated motor-neuron actin/outgrowth role, bounded by the complete accessible abstract and original curator interpretation for finer assays. It does not imply that C9orf72 itself phosphorylates cofilin or polymerizes actin. The ortholog and PAINT rows are consistent with this evidence, not assessed by donor count. Supporting Evidence: |
| GO:0110053 regulation of actin filament organization | IMP PMID:27723745 C9ORF72 interaction with cofilin modulates actin dynamics in... | KEEP AS NON CORE | Summary: C9orf72 regulates axonal actin dynamics and neuronal outgrowth. Reason: PMID:27723745 reports C9orf72-dependent ARF6/RAC1–LIMK/cofilin regulation and rescue by dominant-negative ARF6. This supports the curated motor-neuron actin/outgrowth role, bounded by the complete accessible abstract and original curator interpretation for finer assays. It does not imply that C9orf72 itself phosphorylates cofilin or polymerizes actin. The ortholog and PAINT rows are consistent with this evidence, not assessed by donor count. Supporting Evidence: PMID:27723745 reduced axonal actin dynamics |
| GO:1902774 late endosome to lysosome transport | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific late-endosome-to-lysosome transport assignment needs donor-level resolution. Reason: Broad endolysosomal and autophagic-fusion functions are supported, but they are not interchangeable with this exact transport route. The mouse Q6DFW0 donor assertion is preserved; its precise supporting assay was not recovered in this review. Unchanged EGFR degradation in the particular PMID:37821429 cell system does not refute all contexts, and a human-only evidence requirement is not imposed. Supporting Evidence: |
| GO:1902774 late endosome to lysosome transport | ISS GO_REF:0000024 | UNDECIDED | Summary: The specific late-endosome-to-lysosome transport assignment needs donor-level resolution. Reason: Broad endolysosomal and autophagic-fusion functions are supported, but they are not interchangeable with this exact transport route. The mouse Q6DFW0 donor assertion is preserved; its precise supporting assay was not recovered in this review. Unchanged EGFR degradation in the particular PMID:37821429 cell system does not refute all contexts, and a human-only evidence requirement is not imposed. Supporting Evidence: |
| GO:1903432 regulation of TORC1 signaling | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: C9orf72 modulates nutrient-responsive mTORC1 signaling. Reason: PMID:27559131 measures impaired S6 rephosphorylation after amino-acid refeeding in C9orf72 single-knockout cells, with different SMCR8 single- and double-knockout phenotypes. mTOR localization remains regulated, and direct mTOR inhibition does not reproduce C9orf72 lysosomal recruitment. Retain the broad regulation term without inventing a uniform direction, Rag-GAP activity, or C9orf72 kinase activity. Supporting Evidence: |
| GO:1903432 regulation of TORC1 signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: C9orf72 modulates nutrient-responsive mTORC1 signaling. Reason: PMID:27559131 measures impaired S6 rephosphorylation after amino-acid refeeding in C9orf72 single-knockout cells, with different SMCR8 single- and double-knockout phenotypes. mTOR localization remains regulated, and direct mTOR inhibition does not reproduce C9orf72 lysosomal recruitment. Retain the broad regulation term without inventing a uniform direction, Rag-GAP activity, or C9orf72 kinase activity. Supporting Evidence: |
| GO:1903432 regulation of TORC1 signaling | IMP PMID:27559131 C9orf72 binds SMCR8, localizes to lysosomes, and regulates m... | KEEP AS NON CORE | Summary: C9orf72 modulates nutrient-responsive mTORC1 signaling. Reason: PMID:27559131 measures impaired S6 rephosphorylation after amino-acid refeeding in C9orf72 single-knockout cells, with different SMCR8 single- and double-knockout phenotypes. mTOR localization remains regulated, and direct mTOR inhibition does not reproduce C9orf72 lysosomal recruitment. Retain the broad regulation term without inventing a uniform direction, Rag-GAP activity, or C9orf72 kinase activity. Supporting Evidence: |
| GO:1990316 Atg1/ULK1 kinase complex | IDA PMID:27193190 The ALS/FTLD associated protein C9orf72 associates with SMCR... | KEEP AS NON CORE | Summary: C9orf72 associates with the ULK1 initiation machinery. Reason: PMID:27193190 reports association of the C9orf72/SMCR8/WDR41 assembly with FIP200/ULK1/ATG13/ATG101; PMID:27334615 further supports trafficking-related interaction. Preserve the original colocalization assertion without converting it to stable holo-complex membership or assigning ULK1 kinase activity to C9orf72. |
| GO:2000785 regulation of autophagosome assembly | IMP PMID:27334615 The C9orf72 protein interacts with Rab1a and the ULK1 comple... | ACCEPT | Summary: C9orf72 regulates autophagosome assembly through recruitment of initiation machinery. Reason: PMID:27334615 shows C9orf72-dependent Rab1A/ULK1-complex trafficking and autophagy induction in human cells and primary rat neurons with human rescue. The protein performs recruitment-related molecular work; altered ULK1 catalytic activation was not the measured defect. This is a supported regulatory role rather than transfer of ULK1 kinase function. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which defined C9orf72, C9orf72–SMCR8 and C9orf72–SMCR8–WDR41 preparations account for the reported Rab exchange versus ARF/Rab GAP activities, and which nucleotide states, stoichiometries and membrane conditions determine physiological substrate preference?
Q: Can independent endogenous isoform-specific detection resolve the proposed short-product nuclear membrane pool and extracellular C9orf72, while distinguishing antibody cross-reactivity, fixation effects and low abundance?
Q: Does the Rab1A–ULK1 recruitment mechanism warrant a more specific molecular-adaptor annotation after direct assessment of the coordinated interfaces, beyond the existing small-GTPase-binding and assembly-regulation assertions?
Q: How do loss of normal C9orf72 protein, expanded repeat RNA and dipeptide-repeat products contribute separately to synaptic and stress responses in human cells?
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