CLN6 is a multipass endoplasmic-reticulum membrane protein involved in the delivery of newly synthesized lysosomal enzymes. Together with CLN8, it recruits enzyme precursors at the ER, while CLN8 subsequently accompanies cargo toward the Golgi. CLN6 forms homodimers and exposes luminal regions involved in recruitment. Its deficiency impairs lysosomal degradative capacity and causes neuronal ceroid lipofuscinosis, with progressive neurological and visual dysfunction. Secondary cellular observations include altered lipid distribution and lysosomal pH.
Definition: Selective association with newly synthesized soluble lysosomal enzyme precursors that recruits them to an endoplasmic-reticulum resident complex for subsequent Golgi delivery.
Justification: CLN6 and CLN8 cooperate in enzyme recruitment, while CLN8 mediates subsequent COPII export. A recruitment activity describes the demonstrated contribution without asserting that CLN6 directly binds the coat, independently escorts cargo, or structurally holds the complex together. Ontology parent placement remains to be assessed. The current GO:0038024 cargo receptor activity definition requires a membrane-spanning receptor to engage cargo and coat adaptors together for vesicle delivery. CLN6 remains ER-resident in the tested recruitment system, and simultaneous CLN6 cargo/coat-adaptor engagement is not established; CLN8 supplies the demonstrated export role. GO:0038024 is therefore not asserted for CLN6 from these experiments.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001573 ganglioside metabolic process | IMP PMID:16857350 Gene expression profiling in vLINCL CLN6-deficient fibroblas... | UNDECIDED | Summary: The exact ganglioside-metabolism assertion remains unresolved. Reason: The selected primary abstract reports investigation of gangliosides and cholesterol, but does not expose the ganglioside assay outcome needed to adjudicate this IMP assertion. Full-body attempts have not yet supplied that experiment. CLN6-related lipid abnormalities are plausible, but neither a ganglioside reaction nor its absence is established by the accessible scope. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17237713 Neuronal ceroid lipofuscinosis: a common pathway? | MODIFY | Summary: Refine the verified CLN3 association to transporter binding. Reason: The original human-cell co-immunoprecipitation and tagged-cell controls support the CLN6–CLN3 pair. Independent human CLN3 current and selectivity experiments establish its channel class, which fits transmembrane transporter binding. This refinement describes CLN6 binding a transporter; it does not confer chloride conductance or physiological channel regulation on CLN6. Proposed replacements: transmembrane transporter binding |
| GO:0005515 protein binding | IPI PMID:19235893 Protein product of CLN6 gene responsible for variant late-on... | KEEP AS NON CORE | Summary: Retain the experimentally demonstrated DPYSL2/CRMP-2 association. Reason: A human fetal-brain library screen used the CLN6 N-terminal 1–15 segment, and full-length tagged proteins co-immunoprecipitated in NIH3T3 cells. These experiments support binding. CRMP-2 regulates microtubule-associated neuronal behavior, but the inspected source does not establish the precise cytoskeletal-component binding class or an autonomous cytoskeletal activity of CLN6. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19941651 Novel interactions of CLN5 support molecular networking betw... | KEEP AS NON CORE | Summary: Retain the CLN5 interaction with its actual mouse-partner scope. Reason: The source uses mouse GST-Cln5 residues 26–341 with human CLN6 expressed in COS1 cells and also retrieves endogenous CLN6 from HeLa lysate. GST and LAMP1 controls support the association. The supplied Q3UMW8 identity is the mouse partner actually used; this is not a wrong-gene assignment, and the assay does not assign CLN5 chemistry to CLN6. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:30177828 An orthogonal proteomic survey uncovers novel Zika virus hos... | KEEP AS NON CORE | Summary: Retain the source-specific viral-protein association. Reason: Four literal target records include three anti-tag co-immunoprecipitation observations and one confocal colocalization observation. The viral construct is recorded as A0A142I5B9 residues 2247–2520. The physical assays support association, whereas colocalization alone is not binding evidence. No general viral-function or full-polyprotein mechanism is assigned to CLN6. 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 positive SLC22A23 isoform 2 screen interaction. Reason: The exact human CLN6–SLC22A23 isoform 2 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The exact substrate and physiological role of this SLC22A23 product remain insufficiently defined here for a narrower informative class. 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 positive EBAG9 screen interaction. Reason: The exact human CLN6–EBAG9 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. No specific binding class is established for this EBAG9 association in the inspected evidence. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–SLC30A4 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. SLC30A4 belongs to the CDF transporter family and is annotated as a probable proton-coupled zinc antiporter; the refinement uses that transporter class without claiming that this interaction demonstrates its precise substrate flux. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–TMPRSS2 isoform 2 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The tested TMPRSS2 isoform retains the peptidase S1 domain. Current sequence reconstruction adds 37 N-terminal residues in isoform 2, producing 529 residues; the recorded sufficient region 38–529 therefore retains the protease region. Proposed replacements: protease binding 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 positive CLDN7 screen interaction. Reason: The exact human CLN6–CLDN7 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. A claudin association does not by itself identify CLN6 as a junctional structural protein. 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 positive CD79A screen interaction. Reason: The exact human CLN6–CD79A pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The pair does not assign B-cell receptor signaling to CLN6. 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 positive EVI2B isoform 2 screen interaction. Reason: The exact human CLN6–EVI2B isoform 2 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The source records a sufficient interaction region at residues 16–463; that fragment scope is retained rather than generalized to every EVI2B product. 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 positive KIR2DL3 screen interaction. Reason: The exact human CLN6–KIR2DL3 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The receptor association does not establish an immune-signaling function of CLN6. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–GJA8/connexin 50 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. GJA8 is a pore-forming connexin of gap-junction channels. The transporter-binding term captures its verified partner class without asserting that CLN6 forms or regulates the pore. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–STX1A pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. STX1A is a syntaxin; the literal pair supports syntaxin binding without implying that CLN6 itself is a SNARE or catalyzes membrane fusion. Proposed replacements: syntaxin binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–ARL13B pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. ARL13B is an Arf-family small GTPase-superfamily protein. The class refinement does not depend on resolving its reported weak or uncertain intrinsic hydrolysis and does not assign GEF or GAP chemistry to CLN6. Proposed replacements: small GTPase binding 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 positive FAM209A screen interaction. Reason: The exact human CLN6–FAM209A pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The FAM209A pair has no verified narrower functional class in the inspected sources. 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 positive GORAB screen interaction. Reason: The exact human CLN6–GORAB pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The source specifies a sufficient GORAB region at residues 1–221. GORAB-associated Golgi functions are not transferred to CLN6. 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 positive RIC3 isoform 5 screen interaction. Reason: The exact human CLN6–RIC3 isoform 5 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The exact isoform identifier is retained. Current RIC3 sequence-feature labels and isoform mappings are not fully consistent, so a folding-chaperone class is not assigned to this particular tested product. 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 positive CPLX4 screen interaction. Reason: The exact human CLN6–CPLX4 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. CPLX4 is a SNARE regulator, which is not equivalent to the partner itself being a syntaxin or SNARE. 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 positive CLEC10A screen interaction. Reason: The exact human CLN6–CLEC10A pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The lectin partner identity does not assign carbohydrate binding to CLN6. 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 positive TMEM139 screen interaction. Reason: The exact human CLN6–TMEM139 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. No informative narrower partner class is established for TMEM139 here. 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 positive LRRC25 screen interaction. Reason: The exact human CLN6–LRRC25 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The LRRC25 pair is positive, while its physiological role with CLN6 remains unresolved. 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 positive CISD2 screen interaction. Reason: The exact human CLN6–CISD2 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The CISD2 association does not assign metal-cluster carriage or BCL2 regulation to CLN6. 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 positive FNDC9 screen interaction. Reason: The exact human CLN6–FNDC9 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The FNDC9 association has no verified narrower functional class in this review. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Refine the measured association by the verified partner class. Reason: The exact human CLN6–CREB3L1 pair has 5 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. CREB3L1 is a membrane-tethered precursor containing the DNA-binding bZIP region of its transcription-factor product. The measured association supports this partner class; it does not establish CLN6-dependent transcription, partner processing or nuclear coactivation. Proposed replacements: DNA-binding transcription factor binding 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 positive TMEM237 isoform 2 screen interaction. Reason: The exact human CLN6–TMEM237 isoform 2 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. The exact TMEM237 isoform is retained without extending the result to every product or to ciliary assembly. 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 positive CYBC1 screen interaction. Reason: The exact human CLN6–CYBC1 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. CYBC1 has an assembly/chaperone role for cytochrome b-245. The inspected identity evidence does not resolve the nascent/unfolded-substrate scope of the current protein-folding chaperone-binding definition. 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 positive LIME1 screen interaction. Reason: The exact human CLN6–LIME1 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. LIME1 association does not itself establish lymphocyte signaling by CLN6. 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 positive TEX264 screen interaction. Reason: The exact human CLN6–TEX264 pair has 3 curated records from the HuRI yeast two-hybrid screen. The source distinguishes array, pooling and pairwise validation observations; these are positive assay evidence, not independent proof of native mechanism. TEX264 association does not establish that CLN6 performs ER-phagy receptor activity. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Refine the WWP2 interaction to ubiquitin-ligase binding. Reason: Three exact records in the neurodegenerative-disease interaction screen support the human CLN6–WWP2 pair. WWP2 is a HECT E3 ubiquitin ligase, satisfying the binding-class definition. The screen does not demonstrate ubiquitination of CLN6 or ligase catalysis by CLN6. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Refine the EPHB2 interaction to receptor-tyrosine-kinase binding. Reason: Three exact records in the neurodegenerative-disease interaction screen name P29323-3. Its current sequence changes retain the protein-kinase domain and receptor architecture. Receptor tyrosine kinase binding captures that partner class, without implying CLN6 phosphorylation, kinase activity or a native signaling mechanism. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: |
| GO:0005769 early endosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited early-endosome localization as secondary context. Reason: The target self-donor has independent Rab4-positive early-endosome colocalization in the original human-cell work. This is legitimate experimental grounding for PAINT, not circularity. The historical ancestral-node placement was not reconstructed; the dominant ER recruitment role does not refute the positive secondary localization. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN008358593 SUPPORTS TRANSFER Qualified support from the current target-specific experimental assertion and source assessment. The historical ancestral node, tree and alignment were not reconstructed. Target self-inclusion is legitimate experimental grounding. |
| GO:0005769 early endosome | IDA PMID:17237713 Neuronal ceroid lipofuscinosis: a common pathway? | KEEP AS NON CORE | Summary: Retain the measured Rab4-positive localization. Reason: The full primary source reports CLN6 colocalization with Rab4 in normal human cells. Selected-plane colocalization supports the compartment assertion while leaving trafficking direction and a specific endosomal molecular mechanism unresolved. This secondary observation is compatible with the independently established major ER pool. Supporting Evidence: |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Accept the immunofluorescence-supported ER localization. Reason: The current HPA target XML identifies CLN6 and Q9NWW5 and lists the ER as its main ICC/IF compartment, with an approved overall assessment and supported human-cell staining. This independently agrees with the original CLN6 localization experiments. Original HPA image pixels were not inspected. |
| GO:0005783 endoplasmic reticulum | IDA PMID:15265688 CLN6, which is associated with a lysosomal storage disease, ... | ACCEPT | Summary: Accept the primary ER localization. Reason: The original abstract explicitly reports endogenous human CLN6 detection and ER localization of human GFP-tagged CLN6 in HEK293 cells, including disease mutants. Full Methods were not recovered for this source, but the reported result is direct and independently corroborated by the inspected 2004 and 2020 studies. |
| GO:0005783 endoplasmic reticulum | IDA PMID:19941651 Novel interactions of CLN5 support molecular networking betw... | ACCEPT | Summary: Accept ER localization in the CLN5 interaction study. Reason: Actual HeLa localization experiments retain the CLN6 ER pool while testing CLN5 transport and interactions. The mouse GST-Cln5 reagent in separate biochemical experiments does not convert these human CLN6 localization observations into a mouse-only result. Supporting Evidence: |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: Accept the UniProt ER-location mapping. Reason: The supplied SL-0095 mapping agrees with direct human CLN6 imaging and the ER-resident enzyme-recruitment role. This location inference does not assert that CLN6 is transported with cargo to the Golgi. |
| GO:0005788 endoplasmic reticulum lumen | IBA GO_REF:0000033 | MODIFY | Summary: Refine the activity-location annotation to the ER membrane under GO membrane-protein guidance. Reason: CLN6 is a multipass ER membrane protein. Original human CLN6 engineered-glycosylation experiments establish a luminal loop, and the later enzyme-recruitment study supports a functional luminal interface. GO membrane-protein guidance recommends annotating transmembrane proteins to the membrane itself, supporting GO:0005789 while preserving that luminal biology. This is a representation refinement of the unchanged source assertion, not evidence against recruitment or an error in the uninspected historical PAINT node. Target self-donor evidence remains legitimate. Comparator database queries are corroborating annotation metadata, not primary evidence for CLN6 topology or function. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN008358593 SUPPORTS TRANSFER Target topology and luminal-loop enzyme-association experiments provide positive grounding for the activity-location inference. The preferred membrane replacement follows GO representation guidance, not a claim that luminal activity is false or that the historical PAINT placement was wrong; that placement was not reconstructed. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:15010453 Defective endoplasmic reticulum-resident membrane protein CL... | MODIFY | Summary: Refine whole-product localization to the ER membrane. Reason: The original human CLN6 I153S assay in BHK21 cells introduces an endo-H- and PNGase-F-sensitive glycan into a luminal loop. It establishes loop exposure, while imaging and multipass topology locate the protein in the ER membrane. Refine the located_in term accordingly; retain the original qualifier and source. The separate is_active_in assertion preserves the luminal recruitment evidence and is likewise refined to ER membrane under GO membrane-protein guidance. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:15010453 epitope-tagged CLN6 was shown to be retained in the endoplasmic reticulum (ER) |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accept the ER-membrane localization. Reason: The SL-0097 mapping is consistent with the multipass sequence and direct human CLN6 ER imaging. The membrane location is the most informative representative compartment for its recruitment role. |
| GO:0007042 lysosomal lumen acidification | IBA GO_REF:0000033 | UNDECIDED | Summary: Keep the inherited acidification allocation unresolved. Reason: The target experimental premise reports elevated lysosomal pH in one CLN6-locus-linked patient line. That observation is retained, but the paper leaves direct versus indirect effects unresolved. Later enzyme-recruitment experiments do not identify a CLN6-performed acidification step. An auxiliary role could qualify without proton pumping; it is not yet established here. This uncertainty does not allege erroneous ancestral placement or invalidate target self-donor evidence. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN002701722 UNRESOLVED The current target IMP premise supports a pH phenotype; whether it establishes product participation in acidification remains unresolved. Historical PAINT node placement was not reconstructed, and self-inclusion is not treated as circular. |
| GO:0007042 lysosomal lumen acidification | IMP PMID:11722572 Elevated lysosomal pH in neuronal ceroid lipofuscinoses (NCL... | UNDECIDED | Summary: Preserve the pH observation while leaving process participation unresolved. Reason: Actual Methods, Table 1 and Discussion of PMID:11722572 compare one control with one patient line linked to the CLN6 locus before molecular identification. The line has elevated lysosomal pH, but the authors leave a direct or indirect mechanism open. Neither this experiment nor the later enzyme-recruitment work identifies the step CLN6 performs in acidification. UNDECIDED concerns that functional allocation, not the measured phenotype or a requirement that CLN6 itself pump protons. Supporting Evidence: PMID:11722572 Elevated lysosomal pH was detected in all NCL forms except CLN2 and CLN8. |
| GO:0008203 cholesterol metabolic process | IMP PMID:16857350 Gene expression profiling in vLINCL CLN6-deficient fibroblas... | KEEP AS NON CORE | Summary: Retain the reported cholesterol-distribution phenotype. Reason: The original abstract explicitly reports prominent lysosomal cholesterol accumulation in CLN6-deficient fibroblasts. This supports the existing broad phenotype-linked metabolic assertion at non-core scope, without identifying a cholesterol reaction or autonomous cholesterol carrier performed by CLN6. Detailed full-body assays remain unavailable. Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | UNDECIDED | Summary: The exact NK-cell proteomic target observation remains unresolved. Reason: The selected source is abstract-only and the target table has not been recovered. CLN6 membrane residence is independently well supported, but those independent localization studies do not authenticate the exact NK-cell HDA observation. The original source assertion is preserved pending its target-table inspection. Supporting Evidence: |
| GO:0016020 membrane | NAS PMID:11727201 The gene mutated in variant late-infantile neuronal ceroid l... | MODIFY | Summary: Specify the ER membrane from independent direct evidence. Reason: PMID:11727201 predicts a multipass human membrane protein. Independent human-cell localization and engineered-glycosylation experiments, followed by the CLN6–CLN8 recruitment study, identify the ER membrane as the supported compartment. Refine this broad NAS assertion without changing its original source or conflating it with the unresolved NK-cell HDA record. Proposed replacements: endoplasmic reticulum membrane |
| GO:0030163 protein catabolic process | NAS PMID:10740217 Batten's disease: clues to neuronal protein catabolism in ly... | UNDECIDED | Summary: Leave the historical protein-catabolism assignment unresolved. Reason: The pre-identification review PMID:10740217 proposes a degradative-pathway role, but its full text is unavailable here. Later CLN6 experiments establish reduced substrate degradation and a performed upstream enzyme-recruitment step. They do not settle whether that trafficking contribution belongs within the asserted protein-breakdown process or acts upstream of it. A nonenzymatic participant could qualify; the remaining process boundary warrants UNDECIDED, not a claim that the phenotype is false or that only proteases participate. |
| GO:0030203 glycosaminoglycan metabolic process | IMP PMID:16857350 Gene expression profiling in vLINCL CLN6-deficient fibroblas... | UNDECIDED | Summary: Leave the exact glycosaminoglycan evidence unresolved. Reason: The available PMID:16857350 abstract describes extracellular-matrix transcript changes, but the relevant full-body experiments remain inaccessible after bounded recovery attempts. Those positive findings do not identify every assay supporting the specific glycosaminoglycan assertion. Retain UNDECIDED rather than inferring that the curator relied only on the abstract or that altered transcript abundance proves a CLN6-performed metabolic step. Supporting Evidence: |
| GO:0035727 lysophosphatidic acid binding | IDA PMID:18317235 CLN3p impacts galactosylceramide transport, raft morphology,... | KEEP AS NON CORE | Summary: Retain the directly reported lysophosphatidic-acid binding. Reason: The authentic full primary source includes a CLN6-positive lipid overlay in Figure 7C. The preparation uses cellular lysate and antibody detection rather than a purified CLN6 affinity measurement. This is a positive secondary binding capability, not evidence that CLN6 executes the paper's proposed CLN3 lipid-carrier mechanism. Supporting Evidence: PMID:18317235 CLN1/CLN2/CLN6 proteins bind to lysophosphatidic acid/sulfatide |
| GO:0042803 protein homodimerization activity | IDA PMID:15010453 Defective endoplasmic reticulum-resident membrane protein CL... | ACCEPT | Summary: Accept the measured homodimerization capability. Reason: Cross-linking of tagged human CLN6 in permeabilized BHK21 cells produces a concentration-dependent dimer-sized species. Independent later co-immunoprecipitation and BiFC corroborate self-association. These assays support homodimerization without establishing the native recruitment complex's exact stoichiometry. |
| GO:0045121 membrane raft | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited membrane-raft localization as secondary context. Reason: The target self-donor has independent human-cell colocalization with a membrane-raft marker. This provides legitimate experimental grounding for the inherited assertion. Historical PAINT node placement was not inspected, and the positive compartment evidence is not rejected because ER residence is more prominent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN008358593 SUPPORTS TRANSFER Qualified support from the current target-specific experimental assertion and source assessment. The historical ancestral node, tree and alignment were not reconstructed. Target self-inclusion is legitimate experimental grounding. |
| GO:0045121 membrane raft | IDA PMID:17237713 Neuronal ceroid lipofuscinosis: a common pathway? | KEEP AS NON CORE | Summary: Retain the original membrane-raft colocalization. Reason: The source reports CLN6 colocalization with alkaline phosphatase in normal human cells. This marker-based observation supports secondary raft association; it does not resolve native raft stoichiometry, lipid transport or a dominant plasma-membrane function. Supporting Evidence: PMID:17237713 CLN2, CLN3, CLN6, and CLN8 proteins co-immunoprecipitate and co-localize to early and/or recycling endosomes and lipid rafts. |
| GO:0045862 positive regulation of proteolysis | IMP PMID:15010453 Defective endoplasmic reticulum-resident membrane protein CL... | KEEP AS NON CORE | Summary: Retain positive regulation of degradative capacity at the measured scope. Reason: A pulse/chase assay shows reduced loss of endocytosed radiolabeled arylsulfatase A in CLN6 patient fibroblasts. The same study finds normal cathepsin D synthesis, sorting and processing in its tested cells. This supports the source-specific regulatory phenotype, not proteolytic catalysis by CLN6 or failure of every lysosomal enzyme. Supporting Evidence: |
| GO:0120146 sulfatide binding | IDA PMID:18317235 CLN3p impacts galactosylceramide transport, raft morphology,... | KEEP AS NON CORE | Summary: Retain the positive sulfatide-binding result. Reason: The original Figure 7C reports a positive CLN6 sulfatide overlay using cellular lysate and immunodetection. The evidence supports this secondary binding capacity despite the title foregrounding CLN3. It does not establish purified affinity, native lipid-carrier chemistry or equivalent binding of both CLN6 products. Supporting Evidence: |
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Download this section (compressed HTML)Q: Does CLN6 directly bridge lysosomal cargo and CLN8, or alter cooperative cargo recognition without a stable bridging geometry?
Suggested experts: ER export and lysosomal enzyme-trafficking specialists
Q: How does the altered N terminus of CLN6 isoform 2 affect localization, self-association and enzyme recruitment?
Suggested experts: CLN6 protein-topology and isoform specialists
Q: Which lipid and pH abnormalities arise directly from CLN6-dependent recruitment, and which follow secondary lysosomal dysfunction?
Suggested experts: Lysosomal physiology specialists
Experiment: Reconstitute defined CLN6, CLN8 and individual enzyme precursors with verified membrane topology. Measure direct contacts, stoichiometry and cargo recruitment, separating pairwise association from simultaneous bridging; sequence-verify the luminal-loop variants because published deletion coordinates disagree.
Hypothesis: CLN6 provides a distinct cargo-recognition contribution to the CLN6–CLN8 system.
Type: Biochemical reconstitution and contact mapping
Experiment: Compare sequence-verified canonical and isoform-2 proteins at matched expression in a CLN6-null background, measuring ER localization, dimerization and synchronized enzyme export with a secretory-cargo control.
Hypothesis: The alternative N terminus changes CLN6 recruitment function.
Type: Isoform-specific functional complementation
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