C1QTNF5, also called CTRP5, is a secreted collagen-like and globular C1q-domain protein that assembles into trimers and higher-order oligomers. It associates with the apical and lateral surfaces of retinal pigment epithelial and ciliary epithelial cells and interacts with the membrane protein MFRP. In human retinal pigment epithelium, extracellular C1QTNF5 associates with ADIPOR1 and inhibits its downstream AMPK signaling, helping maintain epithelial metabolic and secretory homeostasis. Its effects on AMPK depend on cellular context. Pathogenic variants such as S163R disturb oligomer handling and secretion and cause autosomal dominant late-onset retinal degeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:17122143 Spatial and temporal expression of MFRP and its interaction ... | KEEP AS NON CORE | Summary: C1QTNF5 associates with MFRP in ocular extracts and heterologous expression experiments. Reason: The complete PMID:17122143 abstract explicitly describes immunoprecipitation/immunoblot experiments using mouse eye and human RPE-choroid extracts and full-length proteins in a heterologous system. It supports the exact MFRP partner rather than merely shared expression. No more specific molecular activity of this interaction is established; retain supported generic binding as non-core under the standing project instruction. The complete original assay panels were not inspected. Supporting Evidence: PMID:17122143 interact with each other in ocular tissues file:human/C1QTNF5/C1QTNF5-uniprot.txt |
| GO:0005515 protein binding | IPI PMID:24531000 The macular degeneration-linked C1QTNF5 (S163) mutation caus... | KEEP AS NON CORE | Summary: Recombinant human C1QTNF5 captures mammalian-cell-derived MFRP. Reason: PMID:24531000 Results and Methods describe human C1QTNF5 immobilized on agarose and human MFRP expressed in CHO-K1 cells, solubilized from membranes and retained after stringent washing. This is specific biochemical association but not a purified two-component affinity measurement. Retain the exact MFRP interaction as non-core generic binding; do not infer lipid transport or receptor catalysis from MFRP domain architecture. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The curated HuRI interaction with SGTA is retained as a non-core binding assertion. Reason: The exact source partner is UniProtKB:O43765, independently represented among the preserved UniProt IntAct interactions. The inspected PMID:32296183 primary assay framework uses complementary yeast two-hybrid screens, pairwise retesting and sequence confirmation. The individual C1QTNF5–SGTA supplementary record was not independently inspected; this decision defers to experimental curators for that target edge, without claiming target-specific orthogonal validation or a native physiological mechanism. Supported generic binding is retained under the standing user instruction; no finer molecular function is established. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The curated HuRI interaction with GUCA1A is retained as a non-core binding assertion. Reason: The exact source partner is UniProtKB:P43080, independently represented among the preserved UniProt IntAct interactions. The inspected PMID:32296183 primary assay framework uses complementary yeast two-hybrid screens, pairwise retesting and sequence confirmation. The individual C1QTNF5–GUCA1A supplementary record was not independently inspected; this decision defers to experimental curators for that target edge, without claiming target-specific orthogonal validation or a native physiological mechanism. Supported generic binding is retained under the standing user instruction; no finer molecular function is established. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The curated HuRI interaction with SGTB is retained as a non-core binding assertion. Reason: The exact source partner is UniProtKB:Q96EQ0, independently represented among the preserved UniProt IntAct interactions. The inspected PMID:32296183 primary assay framework uses complementary yeast two-hybrid screens, pairwise retesting and sequence confirmation. The individual C1QTNF5–SGTB supplementary record was not independently inspected; this decision defers to experimental curators for that target edge, without claiming target-specific orthogonal validation or a native physiological mechanism. Supported generic binding is retained under the standing user instruction; no finer molecular function is established. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Extracellular localization is supported by direct C1QTNF5 secretion experiments. Reason: The PAINT IBD record at PTN008355511 is present in the preserved family export and includes experimentally annotated human C1QTNF5 among its descendant evidence. That is legitimate grounding, not circularity. Independent human RPE secretion measurements in PMID:34887495 support the inherited extracellular location; the full ancestral tree/MSA was not re-audited. |
| GO:0005576 extracellular region | IDA PMID:17122142 CTRP5 is a membrane-associated and secretory protein in the ... | ACCEPT | Summary: Wild-type CTRP5 is secreted in the experimental systems described by the original paper. Reason: The complete PMID:17122142 abstract distinguishes wild-type secretion from secretion impaired by S163R in cultured MDCK/COS-7 systems and describes ocular localization in animal tissue. Retain the experimental annotation with curator deference for the detailed constructs. Independent human iPSC-RPE medium measurements in PMID:34887495 directly corroborate extracellular C1QTNF5. |
| GO:0005576 extracellular region | IDA PMID:34887495 AMPK modulation ameliorates dominant disease phenotypes of C... | ACCEPT | Summary: Human RPE secretes C1QTNF5 into apical and basal media. Reason: PMID:34887495 Results and ELISA Methods directly compare conditioned media from healthy and S163R patient-derived human RPE, showing reduced secretion in patient cells. Wild-type gene augmentation increases secretion. The annotation applies to normal extracellular protein, not to intracellular retention of pathogenic heterooligomers. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic extracellular mapping is independently supported in human cells. Reason: The preserved UniProt secreted location and the human RPE secretion experiments in PMID:34887495 corroborate this annotation independently of the mouse orthology component. Preserve the original mapping identifiers and qualifier. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: C1QTNF5 acts at the RPE cell surface as a membrane-associated secreted protein. Reason: The human RPE membrane preparation, apical colocalization and ADIPOR1 co-immunoprecipitation in PMID:34887495 independently support a plasma-membrane-associated functional pool. Retain the IBA assertion; a single listed donor is not evidence against a PAINT inference. This review does not claim intrinsic transmembrane topology or a fresh reconstruction of the PTN002368877 node. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The plasma-membrane orthology annotation agrees with human target evidence. Reason: Human RPE membrane association and the curated UniProt location independently support the transferred location. C1QTNF5 is secreted and associated with membrane partners; this term does not require it to span the membrane. |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Junction-associated CTRP5 localization is reported in mouse RPE and polarized epithelial models. Reason: The indexed primary-paper passage for PMID:17122142 reports CTRP5 colocalization with ZO-1 in mouse RPE and at lateral junctions of confluent MDCK cells. The canonical cache is abstract-only; the additional passage was read from an indexed copy of the primary paper, not from inspected images. This supports retaining the mouse-derived bicellular-tight-junction location with its model context and curator deference. It does not establish that C1QTNF5 constructs the junction or that all human membrane-associated protein is junctional. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | MODIFY | Summary: C1QTNF5 negatively regulates ADIPOR1-dependent signaling in human retinal pigment epithelium. Reason: The broad signal-transduction assertion can be refined to negative regulation of signal transduction (GO:0009968), which covers reducing the rate or extent of signaling. Independent human RPE experiments in PMID:34887495 show receptor association and reduced downstream AMPK phosphorylation after extracellular recombinant C1QTNF5 treatment and wild-type augmentation. This refinement rests on that target evidence rather than assuming the original receptor-ligand inference establishes an activating mechanism. The inhibitory direction is bounded to RPE: PMID:19651784 instead reports AMPK activation and increased fatty-acid oxidation in myocytes, independent of AdipoR1/AdipoR2 depletion. C1QTNF5 performs extracellular regulation; it is not assigned AMPK kinase activity or a tissue-independent inhibitory effect. Proposed replacements: negative regulation of signal transduction |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The broad membrane location encompasses the independently supported cell-surface-associated pool. Reason: Human RPE membrane preparation, apical colocalization and ADIPOR1 co-immunoprecipitation in PMID:34887495 support membrane association, corroborating the transferred location. Accept this compatible ancestor consistently with the plasma-membrane and apical plasma-membrane rows; its breadth alone does not make an established core location non-core. This does not assign integral-membrane topology, every membrane compartment, or a different activity based on the machine qualifier. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The apical plasma membrane is a demonstrated site of C1QTNF5 association and action. Reason: Human healthy RPE apical immunolabeling, membrane co-immunoprecipitation and apical recombinant-protein treatment in PMID:34887495 support the curated apical location. Mouse and polarized epithelial data in PMID:17122142 are consistent corroboration, not the sole basis of the human claim. |
| GO:0016328 lateral plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lateral membrane-associated CTRP5 is supported in ocular and polarized epithelial contexts. Reason: The complete PMID:17122142 abstract describes a lateral-membrane lattice in RPE, and the indexed original-paper passage describes CTRP5 at MDCK lateral junctions. UniProt independently curates the lateral ocular epithelial pool. Retain the location with these model boundaries, outside the principal apical receptor-regulation synthesis. |
| GO:0030133 transport vesicle | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact transport-vesicle localization transferred from mouse remains unresolved. Reason: The original mouse donor experiment and precise vesicle compartment were not independently inspected. Human RPE endosomal staining in PMID:34887495 and the intracellular handling of S163R heterooligomers do not by themselves establish this specific wild-type transport-vesicle assertion. Preserve the source fields and uncertainty rather than infer that secretion automatically proves every trafficking compartment or that mutant retention disproves the annotation. |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:34887495 AMPK modulation ameliorates dominant disease phenotypes of C... | ACCEPT | Summary: Extracellular C1QTNF5 inhibits ADIPOR1-dependent signaling in human RPE. Reason: PMID:34887495 combines native membrane association with ADIPOR1, apical recombinant globular/full-length C1QTNF5 treatment that lowers pAMPK in healthy human RPE, and wild-type augmentation that restores secretion and reduces pAMPK in patient cells. These data support the curated receptor-inhibitor activity in RPE. Direct receptor affinity and variant effects on affinity were modeled rather than measured as a purified binding constant; no AMPK kinase or ADIPOR1 ceramidase activity is assigned to C1QTNF5. Supporting Evidence: PMID:34887495 native CTRP5 acts as an inhibitor for ADIPOR1 receptors file:human/C1QTNF5/C1QTNF5-uniprot.txt |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: C1QTNF5 assembles into collagen-stalk homotrimers that can form higher oligomers. Reason: GO:0005581 collagen trimer is a more specific complex interpretation than an unspecified protein-containing complex. The target has a collagen region with 23 uninterrupted Gly-X-Y repeats, UniProt curates collagen-mediated homotrimerization, and the longer human recombinant construct in PMID:24531000 contains that region and forms trimers and bouquet-like higher assemblies by gel filtration and negative-stain EM. The integrated sequence, curated subunit and architectural evidence supports the collagen-trimer interpretation. Its triple-helical stalk is an architectural inference in these inspected experiments, not a claim of direct high-resolution stalk determination: PMID:22892318 and the crystallographic part of PMID:24531000 resolve only the globular gC1q head. Generic trimerization or the number of asymmetric-unit molecules alone would not establish this term. No particular numbered collagen type, obligatory disulfide linkage, or autonomous cell-adhesion function is inferred. Proposed replacements: collagen trimer |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Human C1QTNF5 self-association independently supports the orthology-derived binding assertion. Reason: PMID:24531000 reports human recombinant oligomers, electron microscopy of bouquet-like assemblies and gC1q-domain intersubunit interfaces. The independent human biochemical and structural evidence corroborates the mouse-derived identical-protein-binding annotation. No covalent disulfide requirement is inferred. PMID:22892318 independently resolves the human isolated globular-head homotrimer and its intersubunit interface; that head construct does not establish the collagen stalk structure. Supporting Evidence: file:human/C1QTNF5/C1QTNF5-uniprot.txt PMID:22892318 The homotrimer is formed by packing the inner layers together. |
| GO:0042802 identical protein binding | IPI PMID:24531000 The macular degeneration-linked C1QTNF5 (S163) mutation caus... | ACCEPT | Summary: C1QTNF5 forms homomeric assemblies through direct intersubunit contacts. Reason: Human recombinant C1QTNF5 oligomerization and structural interfaces in PMID:24531000 support the exact self partner. The study distinguishes stable trimers/higher oligomers from a proposed physiological adhesive role of crystal head-to-head packing; the latter is not treated as a demonstrated cell-adhesion molecular activity. Supporting Evidence: PMID:24531000 C1QTNF5 can form bouquet-like octadecamers file:human/C1QTNF5/C1QTNF5-uniprot.txt |
| GO:0048018 receptor ligand activity | IBA GO_REF:0000033 | UNDECIDED | Summary: The precise receptor-activating interpretation of the inherited ligand term needs resolution. Reason: The preserved PAINT export contains an IBD for GO:0048018 at PTN008355511; the full ancestral tree and donor experiments were not re-audited. Current official GO text describes a receptor activity change, but its is_a parent is signaling receptor activator activity. Human RPE evidence in PMID:34887495 establishes ADIPOR1 inhibition. The complete normal abstract of PMID:19651784 reports myocyte AMPK/ACC activation and increased glucose uptake and fatty-acid oxidation after recombinant C1QTNF5, persisting after depletion of AdipoR1 or AdipoR2. It does not identify an alternative activating receptor or demonstrate that the AMPK response itself is receptor activation. Its detailed target construct and myocyte species were not established from the abstract-only cache. Retain uncertainty about the specific receptor-ligand/activator claim while acknowledging real activating downstream signaling in a different context; neither donor count nor tissue-dependent inhibitory signaling disproves the IBA. |
| GO:0050995 negative regulation of lipid catabolic process | IC PMID:34887495 AMPK modulation ameliorates dominant disease phenotypes of C... | UNDECIDED | Summary: The directional lipid-catabolism inference is not resolved by the inspected RPE experiments. Reason: The IC derives from C1QTNF5 receptor inhibition, but PMID:34887495 separates acute healthy-RPE signaling from chronic S163R disease phenotypes. Healthy-RPE C1QTNF5 inhibits AMPK signaling; chronically elevated AMPK in patient RPE accompanies reduced PEDF/PEDF-R phospholipase activity and impaired photoreceptor-lipid digestion. These observations do not transparently establish that normal C1QTNF5 negatively regulates lipid breakdown. Independently, the complete normal PMID:19651784 abstract directly reports increased fatty-acid oxidation after recombinant C1QTNF5 treatment of myocytes, alongside AMPK/ACC phosphorylation. That is positive lipid catabolism in its assay context and argues against a universal negative effect, but does not by itself falsify a distinct RPE-specific regulatory pathway. Preserve UNDECIDED until the intended directional and temporal IC chain is resolved; do not reverse its sign merely from mutant phenotypes, transfer myocyte effects to RPE, or assign C1QTNF5 a lipase activity. Supporting Evidence: file:human/C1QTNF5/C1QTNF5-uniprot.txt PMID:19651784 stimulated fatty acid oxidation |
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Download this section (compressed HTML)Q: Which receptor, if any, mediates the myocyte AMPK response reported in PMID:19651784 after AdipoR1/AdipoR2 depletion, and how should that response be reconciled with human-RPE ADIPOR1 inhibition and the activator-parent GO:0048018 PAINT assertion?
Q: What exact directional and temporal mechanism underlies the RPE IC annotation for negative regulation of lipid catabolism, given chronic mutant RPE lipid-digestion defects and the independent positive myocyte fatty-acid-oxidation response in PMID:19651784?
Q: Does the C1QTNF5–MFRP partnership execute a defined epithelial adhesion, membrane-organization or lipid-handling step independently of ADIPOR1 regulation? Binding, colocalization and oligomer architecture are established, but a distinct molecular activity or characterized named complex has not been assigned here; no adapter/tether or adhesion term is inferred from association or crystal packing alone.
Q: Which wild-type transport-vesicle compartment and source experiment support the mouse-derived localization annotation, and how does it differ from pathogenic heterooligomer retention?
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