IFT140 (C. elegans CHE-11) is a large WD40-repeat/TPR-repeat subunit of the core of intraflagellar transport complex A (IFT-A), together with IFT122 and IFT144/WDR19; the peripheral IFT-A subcomplex contains IFT43, IFT121/WDR35 and IFT139/TTC21B. IFT-A is carried into the cilium on anterograde IFT trains and then, with cytoplasmic dynein-2, drives retrograde transport of IFT-B, BBSome and membrane cargo from the ciliary tip back to the base. Through its cargo adaptor TULP3, which binds membrane phosphoinositides, IFT-A also mediates ciliary entry of membrane proteins, notably G protein-coupled receptors such as SSTR3, MCHR1, GPR161 and GPR45. IFT140 localizes to the basal body, the axoneme and the ciliary tip. Mutations in IFT140 cause skeletal ciliopathies (Mainzer-Saldino syndrome, Jeune asphyxiating thoracic dystrophy / short-rib thoracic dysplasia 9), retinitis pigmentosa and an adult-onset polycystic kidney disease, and mouse Ift140 is required for photoreceptor outer segment development and opsin delivery.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001750 photoreceptor outer segment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Photoreceptor outer segment (IEA from mouse Ift140). Mouse Ift140 is required for outer segment formation and opsin delivery, and human IFT140 mutations cause retinal degeneration. Reason: Cell-type-specific instance of IFT140's ciliary location (the outer segment is a modified cilium). |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | REMOVE | Summary: Protein binding with IFT144/WDR19 (Q8NEZ3), from a large organelle-specific interactome screen. Reflects IFT-A core assembly. Reason: Generic protein binding is uninformative; IFT-A membership is captured by GO:0030991. |
| GO:0005515 protein binding | IPI PMID:27932497 Intraflagellar transport-A complex mediates ciliary entry an... | REMOVE | Summary: Protein binding with IFT144/WDR19 (Q8NEZ3), visible immunoprecipitation mapping of IFT-A architecture. Reason: Generic protein binding is uninformative; IFT-A membership is captured by GO:0030991 from the same paper. Supporting Evidence: PMID:27932497 A weak interaction was also observed between IFT140 and IFT144. |
| GO:0005515 protein binding | IPI PMID:29220510 Ciliopathy-associated mutations of IFT122 impair ciliary pro... | REMOVE | Summary: Protein binding with IFT144/WDR19 (Q8NEZ3) in a study of IFT122 ciliopathy mutants. Reason: Generic protein binding is uninformative; IFT-A core assembly is captured by GO:0030991. Supporting Evidence: PMID:29220510 As the IFT122 subunit connects the core and peripheral subcomplexes of the IFT-A complex, it is expected to play a pivotal role in the complex. |
| GO:0005515 protein binding | IPI PMID:29220510 Ciliopathy-associated mutations of IFT122 impair ciliary pro... | REMOVE | Summary: Protein binding with IFT144 and IFT122 (Q8NEZ3, Q9HBG6), IFT-A core trimer. Reason: Generic protein binding is uninformative; IFT-A membership is captured by GO:0030991. |
| GO:0005813 centrosome | IDA PMID:23418020 Combined NGS approaches identify mutations in the intraflage... | ACCEPT | Summary: Centrosome (IDA). Flag-tagged IFT140 localizes to centrosomes in most transfected cells. Reason: Direct experimental evidence; the centrosome/basal body is where IFT-A assembles before ciliary entry. Supporting Evidence: PMID:23418020 Although flag-tagged IFT140 localizes to centrosomes in the majority of cells examined |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosome (IEA, UniProt subcellular location). Reason: Corroborated by IDA (PMID:23418020). |
| GO:0005814 centriole | IEA GO_REF:0000107 | ACCEPT | Summary: Centriole (IEA from mouse). IFT140 localizes at the basal body, which is derived from the mother centriole. Reason: Consistent with basal body/centrosome localization. |
| GO:0005929 cilium | IDA PMID:27932497 Intraflagellar transport-A complex mediates ciliary entry an... | ACCEPT | Summary: Cilium (IDA). IFT140 was immunostained in cilia of control and IFT-A knockout RPE1 cells. Reason: Direct evidence; IFT140 is a ciliary IFT-A subunit. Supporting Evidence: PMID:27932497 Localization of IFT88 (U), IFT140 (V), EGFP-IFT43 (W), and EGFP-TULP3 (X) in individual control, IFT139-KO, and IFT144-KO cells was classified as mainly ciliary base, mainly ciliary bulge, base and bulge, throughout the cilium, and no ciliary localization and counted. |
| GO:0005929 cilium | IEA GO_REF:0000120 | ACCEPT | Summary: Cilium (IEA). Reason: Corroborated by IDA. |
| GO:0005929 cilium | NAS PMID:27806291 Role for the IFT-A Complex in Selective Transport to the Pri... | ACCEPT | Summary: Cilium (NAS) from the Wdr35/IFT-A selective transport study. Reason: Correct. Supporting Evidence: PMID:27806291 The primary cilium is derived from centrosomes and is maintained by intraflagellar transport (IFT) particles, including two protein sub-complexes, IFT-A and IFT-B |
| GO:0005929 cilium | TAS Reactome:R-HSA-5610725 | ACCEPT | Summary: Cilium (TAS, Reactome R-HSA-5610725, Hedgehog ciliary trafficking reaction involving IFT-A). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5610726 | ACCEPT | Summary: Cilium (TAS, Reactome R-HSA-5610726). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5617829 | ACCEPT | Summary: Cilium (TAS, Reactome R-HSA-5617829). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5624949 | ACCEPT | Summary: Cilium (TAS, Reactome anterograde IFT train assembly). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5625416 | ACCEPT | Summary: Cilium (TAS, Reactome anterograde IFT). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5625424 | ACCEPT | Summary: Cilium (TAS, Reactome retrograde IFT train dissociation). Reason: Correct location. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5625426 | ACCEPT | Summary: Cilium (TAS, Reactome retrograde IFT). Reason: Correct location. |
| GO:0005930 axoneme | IBA GO_REF:0000033 | ACCEPT | Summary: Axoneme (IBA). IFT trains run along axonemal doublet microtubules. Reason: Phylogenetically supported; IFT-A moves along the axoneme. |
| GO:0005930 axoneme | IEA GO_REF:0000107 | ACCEPT | Summary: Axoneme (IEA from mouse). Reason: Consistent with IBA. |
| GO:0005930 axoneme | ISS GO_REF:0000024 | ACCEPT | Summary: Axoneme (ISS from mouse). Reason: Consistent with IBA. |
| GO:0030991 intraciliary transport particle A | IBA GO_REF:0000033 | ACCEPT | Summary: Part of IFT-A (IBA). Reason: Core identity of IFT140. |
| GO:0030991 intraciliary transport particle A | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: Part of IFT-A (IDA). Purification of the IFT-A complex with TULP3. Reason: Core identity; experimentally supported. Supporting Evidence: PMID:20889716 We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. |
| GO:0030991 intraciliary transport particle A | IDA PMID:27932497 Intraflagellar transport-A complex mediates ciliary entry an... | ACCEPT | Summary: Part of IFT-A (IDA); IFT140 forms the IFT-A core with IFT122 and IFT144. Reason: Core identity. Supporting Evidence: PMID:27932497 proposed that Chlamydomonas IFT122, IFT140, and IFT144 create a stable core, with which IFT43 and IFT139 can interact |
| GO:0030991 intraciliary transport particle A | IDA PMID:36775821 Human IFT-A complex structures provide molecular insights in... | ACCEPT | Summary: Part of IFT-A (IDA); cryo-EM structures of human IFT-A. Reason: Core identity; structural evidence. Supporting Evidence: PMID:36775821 Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0-3.9 |
| GO:0030991 intraciliary transport particle A | IEA GO_REF:0000120 | ACCEPT | Summary: Part of IFT-A (IEA). Reason: Core identity. |
| GO:0030991 intraciliary transport particle A | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | ACCEPT | Summary: Part of IFT-A (IPI), organelle-specific interactome. Reason: Core identity. Supporting Evidence: PMID:27173435 Known complexes include those in ciliary transport (IFT-A and -B, the BBSome and KIF3 complex) |
| GO:0032391 photoreceptor connecting cilium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Photoreceptor connecting cilium (IEA from mouse). Reason: Cell-type-specific ciliary location, consistent with retinal disease and mouse photoreceptor studies. |
| GO:0035720 intraciliary anterograde transport | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: Intraciliary anterograde transport (IDA). IFT-A is itself carried anterogradely with IFT-B and is required for ciliary entry of membrane cargo (GPCRs) via TULP3. Reason: IFT-A participates in anterograde delivery of membrane cargo into cilia, although its best-known role is retrograde. Supporting Evidence: PMID:27932497 In control cells, the IFT-A complex is required for ciliary entry of GPCRs and anterogradely trafficked along with the IFT-B complex. |
| GO:0035720 intraciliary anterograde transport | IDA PMID:40472089 GPR45 modulates GΞ±(s) at primary cilia of the paraventricula... | ACCEPT | Summary: Intraciliary anterograde transport (IDA), from a study of TULP3-dependent ciliary localization of GPR45. The cached full text describes TULP3 as an IFT-A adapter but IFT140 assays were not found in the cached text (possibly in supplementary data). Reason: Biologically correct for IFT-A; deferring to the curator on the specific experimental evidence. Supporting Evidence: PMID:40472089 TUB and TULP3 function as adapters of the highly conserved intraflagellar complex-A (IFT-A) complex in ciliary trafficking |
| GO:0035721 intraciliary retrograde transport | IBA GO_REF:0000033 | ACCEPT | Summary: Intraciliary retrograde transport (IBA). Reason: Core process of IFT-A. |
| GO:0035721 intraciliary retrograde transport | IEA GO_REF:0000117 | ACCEPT | Summary: Intraciliary retrograde transport (IEA, ARBA). Reason: Core process. |
| GO:0035721 intraciliary retrograde transport | IMP PMID:22503633 Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mu... | ACCEPT | Summary: Intraciliary retrograde transport (IMP). Fibroblasts from IFT140-mutant Mainzer-Saldino patients show altered retrograde transport and redistribution of IFT-B proteins. Reason: Experimental evidence in human patient cells. Supporting Evidence: PMID:22503633 the data we report further support the view that alterations of IFT-A components disorganize assembly and/or maintenance of ciliary structure by impairing retrograde IFT through the redistribution of ciliary proteins (notably IFT-B complex components) |
| GO:0035721 intraciliary retrograde transport | NAS PMID:27806291 Role for the IFT-A Complex in Selective Transport to the Pri... | ACCEPT | Summary: Intraciliary retrograde transport (NAS). Reason: Core process. Supporting Evidence: PMID:27806291 IFT-B and IFT-A were shown to regulate anterograde and retrograde IFT within the cilium, respectively |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: Ciliary basal body (IBA). Reason: Consistent with IDA in RPE1 cells. |
| GO:0036064 ciliary basal body | IDA GO_REF:0000052 | ACCEPT | Summary: Ciliary basal body (IDA, immunofluorescence curation). Reason: Consistent with other evidence. |
| GO:0036064 ciliary basal body | IDA PMID:22503633 Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mu... | ACCEPT | Summary: Ciliary basal body (IDA). Wild-type Flag-IFT140 predominantly localizes to basal bodies in RPE1 cells. Reason: Direct experimental evidence. Supporting Evidence: PMID:22503633 whereas the wild-type Flag-tagged IFT140 protein predominantly localized to the basal bodies in RPE1 cells |
| GO:0036064 ciliary basal body | IEA GO_REF:0000120 | ACCEPT | Summary: Ciliary basal body (IEA). Reason: Corroborated by IDA. |
| GO:0060271 cilium assembly | IEA GO_REF:0000117 | ACCEPT | Summary: Cilium assembly (IEA, ARBA). Reason: IFT-A contributes to cilium assembly and maintenance; IFT140 loss affects ciliogenesis to a lesser extent than IFT-B loss. |
| GO:0060271 cilium assembly | IMP PMID:28724397 Partial uniparental isodisomy of chromosome 16 unmasks a del... | ACCEPT | Summary: Cilium assembly (IMP), zebrafish ift140 morphant and complementation assays for a Mainzer-Saldino IFT140 variant. Reason: Supported by experimental data and general IFT-A biology. Supporting Evidence: PMID:28724397 an assay of missense variants through an in vivo complementation approach [49] is highly concordant with in vitro cilia length complementation studies |
| GO:0060271 cilium assembly | NAS PMID:27806291 Role for the IFT-A Complex in Selective Transport to the Pri... | ACCEPT | Summary: Cilium assembly (NAS). Reason: Correct. Supporting Evidence: PMID:27806291 The primary cilium is derived from centrosomes and is maintained by intraflagellar transport (IFT) particles, including two protein sub-complexes, IFT-A and IFT-B |
| GO:0061512 protein localization to cilium | IMP PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: Protein localization to cilium (IMP, acts upstream of or within). IFT-A knockdown reduces ciliary localization of GPCRs via TULP3. Reason: Core process; IFT-A with TULP3 directs ciliary entry of GPCRs. Supporting Evidence: PMID:20889716 TULP3 and IFT-A, in turn, promote trafficking of a subset of G protein-coupled receptors (GPCRs), but not Smoothened, to cilia. |
| GO:0061512 protein localization to cilium | IMP PMID:22503633 Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mu... | ACCEPT | Summary: Protein localization to cilium (IMP). Altered ciliary abundance and localization of IFT proteins in patient fibroblasts. Reason: Consistent with IFT140's role in ciliary protein trafficking. Supporting Evidence: PMID:22503633 Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals |
| GO:0097499 protein localization to non-motile cilium | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: Protein localization to non-motile cilium (IDA). IFT-A directs ciliary entry of TULP3 and GPCRs into primary cilia. Reason: Core process. Supporting Evidence: PMID:20889716 we find that the IFT-A complex has a second role directing ciliary entry of TULP3 |
| GO:0097499 protein localization to non-motile cilium | IDA PMID:36775821 Human IFT-A complex structures provide molecular insights in... | ACCEPT | Summary: Protein localization to non-motile cilium (IDA); TULP3 interface mutants that disrupt IFT-A binding impair cargo transport. Reason: Core process; structural and functional evidence. Supporting Evidence: PMID:36775821 TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. |
| GO:0097499 protein localization to non-motile cilium | IDA PMID:40472089 GPR45 modulates GΞ±(s) at primary cilia of the paraventricula... | ACCEPT | Summary: Protein localization to non-motile cilium (IDA), GPR45 ciliary localization study (TULP3/IFT-A dependent). Reason: Biologically correct; deferring to the curator on the specific experimental evidence. Supporting Evidence: PMID:40472089 TUB and TULP3 function as adapters of the highly conserved intraflagellar complex-A (IFT-A) complex in ciliary trafficking |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5624952 | ACCEPT | Summary: Ciliary tip (TAS, Reactome). Retrograde trains, including IFT-A, assemble at the ciliary tip. Reason: Correct; IFT-A accumulates at bulged tips in some IFT-A mutants (PMID:27932497). |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5625416 | ACCEPT | Summary: Ciliary tip (TAS, Reactome anterograde IFT). Reason: Correct. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5625421 | ACCEPT | Summary: Ciliary tip (TAS, Reactome anterograde train dissociation). Reason: Correct. |
| GO:0097542 ciliary tip | TAS Reactome:R-HSA-5625426 | ACCEPT | Summary: Ciliary tip (TAS, Reactome retrograde IFT). Reason: Correct. |
| GO:0097730 non-motile cilium | IEA GO_REF:0000107 | ACCEPT | Summary: Non-motile cilium (IEA from mouse). Reason: IFT140 functions in primary cilia (GPCR trafficking, Hedgehog signalling). |
| GO:0140597 protein carrier activity | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: Contributes to protein carrier activity (IDA). IFT-A, bridging TULP3 and membrane phosphoinositides, carries GPCR cargo into cilia. Reason: Appropriate contributes_to annotation for a subunit of the cargo-carrying IFT-A complex. Supporting Evidence: PMID:20889716 Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. |
| GO:0140597 protein carrier activity | IDA PMID:36775821 Human IFT-A complex structures provide molecular insights in... | ACCEPT | Summary: Contributes to protein carrier activity (IDA); human IFT-A structure with TULP3 cargo adapter. Reason: Appropriate contributes_to annotation. Supporting Evidence: PMID:36775821 TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. |
| GO:1902017 regulation of cilium assembly | IMP PMID:22503633 Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mu... | MODIFY | Summary: Regulation of cilium assembly (IMP), Mainzer-Saldino patient fibroblasts. IFT140 is part of the IFT machinery that builds and maintains cilia rather than a regulator. Reason: Cilium assembly (GO:0060271) better captures IFT140's direct participation; the regulation term implies a modulatory role. Proposed replacements: cilium assembly Supporting Evidence: PMID:22503633 alterations of IFT-A components disorganize assembly and/or maintenance of ciliary structure by impairing retrograde IFT |
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Download this section (compressed HTML)Q: Does IFT140 directly contact TULP3 or membrane cargo, or does it act purely as a structural scaffold of the IFT-A core?
Q: How do IFT140 variants causing isolated retinal degeneration or adult polycystic kidney disease differ mechanistically from those causing skeletal ciliopathies?
Experiment: Express structure-guided IFT140 interface mutants in IFT140-knockout RPE1 cells to separate IFT-A assembly, TULP3/GPCR ciliary entry and retrograde transport functions.
Experiment: Live imaging of IFT-A and IFT-B trains in patient-derived IFT140 variant cells to quantify retrograde train frequency and velocity.
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