TULP3 is a tubby-family adaptor that delivers integral membrane proteins into the primary cilium. Its C-terminal tubby domain binds PI(4,5)P2 and captures ciliary localization sequences of cargo such as rhodopsin-family GPCRs (GPR161, SSTR3, MCHR1, FFAR4, GPR45) and the polycystin-1/2 complex at the plasma membrane, while its N-terminal region binds the intraflagellar transport complex A (IFT-A), which carries TULP3 and cargo through the ciliary base. Release of cargo is favored by the PI(4,5)P2-poor, PI(4)P-rich ciliary membrane maintained by INPP5E. By importing the Gs-coupled receptor GPR161 into cilia, TULP3 acts as a negative regulator of Sonic hedgehog signalling in neural tube patterning. TULP3 can also translocate to the nucleus upon Gq/PLC-beta-mediated PI(4,5)P2 hydrolysis, and has been reported to interact with SIRT1 and, in mouse, to mediate metabolic responses to lithocholic acid. Biallelic TULP3 variants cause progressive liver, kidney and heart fibrosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001664 G protein-coupled receptor binding | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: TULP3 physically associates with ciliary localization sequences of GPCRs in a PI(4,5)P2-dependent manner. Reason: Proximity biotinylation shows TULP3 interacts with GPCR ciliary-targeting motifs; this cargo-recognition binding is part of its adaptor function. Supporting Evidence: PMID:28154160 As TULP3 determines the trafficking of CLSs from multiple GPCRs and fibrocystin, we tested for physical interactions between the CLS fusions and TULP3. PMID:28154160 The first step involves the capture of membrane cargo by TULP3 in the plasma membrane in a PI(4,5)P2-dependent manner. |
| GO:0005515 protein binding | IPI PMID:22190034 Global landscape of HIV-human protein complexes. | REMOVE | Summary: Interaction with HIV-1 Vpr (P12520) in an HIV-human complex screen. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: PSTPIP1. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: MAGEA6. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: KRTAP10-5. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: KRTAP10-7. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Y2H interactome hit: ROPN1. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex hit: SIRT1. Reason: Generic protein binding; the TULP3-SIRT1 interaction is reported and may be functionally relevant, but protein binding conveys no activity. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex hit: BACH2. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Variant interactome hit: MAGEA6. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Variant interactome hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI hit: PSTPIP1. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI hit: HSF2BP. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI hit: MAGEA6. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI hit: BACH2. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale network hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale network hit: SIRT1. Reason: Generic protein binding; the TULP3-SIRT1 interaction is reported and may be functionally relevant, but protein binding conveys no activity. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proteome-scale network hit: BACH2. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: OpenCell hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:35397207 Progressive liver, kidney, and heart degeneration in childre... | REMOVE | Summary: TULP3 co-immunoprecipitates with SIRT1. Reason: Generic protein binding; the TULP3-SIRT1 interaction is reported and may be functionally relevant, but protein binding conveys no activity. Removal does not imply the interaction is false. Supporting Evidence: PMID:35397207 We co-transfected human TULP3 and SIRT1 in FLAG- and V5-tagged pcDNA6 vectors, respectively, into HEK293T cells by using calcium phosphate transfection. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell map hit: ANKRD54. Reason: Generic protein binding from a proteome-scale interaction screen is uninformative and has no established functional context for TULP3; removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell map hit: SIRT1. Reason: Generic protein binding; the TULP3-SIRT1 interaction is reported and may be functionally relevant, but protein binding conveys no activity. Removal does not imply the interaction is false. |
| GO:0005546 phosphatidylinositol-4,5-bisphosphate binding | NAS PMID:11375483 G-protein signaling through tubby proteins. | ACCEPT | Summary: PI(4,5)P2 binding by the tubby domain. Reason: The tubby domain is a PI(4,5)P2-binding module (structural evidence in tubby), and TULP3 phosphoinositide binding is required for ciliary GPCR trafficking. Core activity. Supporting Evidence: PMID:11375483 Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." PMID:20889716 Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. PMID:28154160 The first step involves the capture of membrane cargo by TULP3 in the plasma membrane in a PI(4,5)P2-dependent manner. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Extracellular region (UniProt, by similarity to mouse; unconventional secretion). Reason: Unconventional secretion of tubby proteins has been proposed from rodent data; no human TULP3 evidence and unrelated to the ciliary trafficking role. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt Secreted {ECO:0000250|UniProtKB:O88413}. Note=Does not have a cleavable |
| GO:0005634 nucleus | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | KEEP AS NON CORE | Summary: TULP3 detected in the nucleus. Reason: TULP3 can translocate to the nucleus upon PI(4,5)P2 hydrolysis; a minor, regulated pool not linked to its ciliary function. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus (UniProt subcellular location). Reason: As above. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0005634 nucleus | NAS PMID:11375483 G-protein signaling through tubby proteins. | KEEP AS NON CORE | Summary: Nucleus (Gq-induced translocation). Reason: As above. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence: nucleoplasm. Reason: HPA main location includes nucleoplasm; consistent with a nuclear pool. Image not inspected. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence: nucleolus. Reason: Antibody-based call without functional context; image not inspected. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm (UniProt subcellular location). Reason: Correct broad location for a peripheral membrane adaptor. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: plasma membrane. Reason: TULP3 captures cargo at the plasma membrane via PI(4,5)P2. Supporting Evidence: PMID:28154160 The first step involves the capture of membrane cargo by TULP3 in the plasma membrane in a PI(4,5)P2-dependent manner. |
| GO:0005886 plasma membrane | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: TULP3-cargo complexes form at the plasma membrane. Reason: Direct localization supporting the capture step. Supporting Evidence: PMID:28154160 The first step involves the capture of membrane cargo by TULP3 in the plasma membrane in a PI(4,5)P2-dependent manner. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (UniProt subcellular location). Reason: Correct. Supporting Evidence: PMID:28154160 The first step involves the capture of membrane cargo by TULP3 in the plasma membrane in a PI(4,5)P2-dependent manner. |
| GO:0005886 plasma membrane | NAS PMID:11375483 G-protein signaling through tubby proteins. | ACCEPT | Summary: Plasma membrane localization through PI(4,5)P2 binding. Reason: Correct. Supporting Evidence: PMID:11375483 Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cilium (tubby family). Reason: Consistent with direct ciliary localization of TULP3. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0005929 cilium | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: primary cilium (Supported). Reason: Agrees with independent experimental localization. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, cilium |
| GO:0005929 cilium | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: IFT-A directs ciliary entry of TULP3. Reason: Direct localization. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0005929 cilium | IDA PMID:27932497 Intraflagellar transport-A complex mediates ciliary entry an... | ACCEPT | Summary: TULP3 localization in cilia analyzed with IFT-A. Reason: Direct localization. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, cilium |
| GO:0005929 cilium | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: TULP3 localizes to cilia. Reason: Direct localization. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0005929 cilium | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic cilium annotation. Reason: Consistent with experimental data. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell projection, cilium |
| GO:0005929 cilium | TAS Reactome:R-HSA-5610725 | ACCEPT | Summary: Reactome: TULP3 in cilium. Reason: Consistent with experimental data. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5610726 | ACCEPT | Summary: Reactome: TULP3 in cilium. Reason: Consistent with experimental data. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0005930 axoneme | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Axoneme transferred from mouse. Reason: TULP3 moves with IFT-A trains along the axoneme and associates with the ciliary membrane; axoneme is a plausible but imprecise location. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:11375483 G-protein signaling through tubby proteins. | MARK AS OVER ANNOTATED | Summary: Regulation of transcription proposed for tubby proteins. Reason: The transcription-regulator model was a hypothesis for the family based on nuclear translocation; no direct evidence shows TULP3 regulates transcription, and its established role is ciliary membrane-protein trafficking. Supporting Evidence: PMID:11375483 These data suggest that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G-protein signaling and the regulation of gene expression. |
| GO:0007186 G protein-coupled receptor signaling pathway | NAS PMID:11375483 G-protein signaling through tubby proteins. | MARK AS OVER ANNOTATED | Summary: GPCR signalling pathway (tubby proteins respond to Gq signalling). Reason: Gq/PLC-beta signalling releases TULP3 from the membrane, i.e. TULP3 responds to this pathway; it is not shown to transduce the signal. Its role toward GPCRs is trafficking them into cilia. Supporting Evidence: PMID:11375483 The localization of tubby-like protein 3 (TULP3) is similarly regulated. |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | KEEP AS NON CORE | Summary: TULP3 regulates ciliary GPCR localization and Hedgehog signalling. Reason: By delivering GPCRs to cilia TULP3 affects their signalling; this is a downstream consequence of the trafficking role. 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:0008277 regulation of G protein-coupled receptor signaling pathway | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | KEEP AS NON CORE | Summary: TULP3-dependent ciliary GPCR trafficking affects signalling. Reason: As above. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IMP PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | KEEP AS NON CORE | Summary: TULP3 loss alters ciliary GPCR levels. Reason: As above. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0019899 enzyme binding | IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi... | KEEP AS NON CORE | Summary: TULP3 interacts with SIRT1 (enzyme binding). Reason: A reported, reproducible interaction with the deacetylase SIRT1 (also by co-IP), possibly linked to TULP3 effects on sirtuin activity; peripheral to the ciliary adaptor function. Supporting Evidence: PMID:35397207 We co-transfected human TULP3 and SIRT1 in FLAG- and V5-tagged pcDNA6 vectors, respectively, into HEK293T cells by using calcium phosphate transfection. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 bridges IFT-A and membrane phosphoinositides/cargo. Reason: TULP3 links two partners (IFT-A and membrane cargo) to promote ciliary entry; protein-macromolecule adaptor activity is the appropriate core MF. Supporting Evidence: PMID:20889716 We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. PMID:20889716 Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:36775821 Human IFT-A complex structures provide molecular insights in... | ACCEPT | Summary: Cryo-EM of IFT-A with TULP3, the cargo adapter. Reason: Structural and functional support for the adaptor role. Supporting Evidence: PMID:36775821 TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. |
| GO:0030674 protein-macromolecule adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Adaptor activity transferred from mouse. Reason: Consistent with human data. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0035091 phosphatidylinositol binding | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 binds membrane phosphoinositides. Reason: Correct; the more specific PI(4,5)P2 binding is also annotated. Supporting Evidence: PMID:20889716 Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. |
| GO:0035720 intraciliary anterograde transport | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | KEEP AS NON CORE | Summary: TULP3 is carried into cilia by IFT-A. Reason: TULP3 is an IFT-A cargo adaptor that rides IFT trains into cilia; it is not a component of the IFT machinery that moves trains, so this process is kept as non-core. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. file:human/TULP3/TULP3-deep-research-falcon.md depleting TULP3 did not itself dismantle IFT-A or IFT-B localization, supporting its classification as an associated adaptor rather than an obligate structural IFT-A subunit. |
| GO:0035720 intraciliary anterograde transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Anterograde IFT transferred from mouse. Reason: As above. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0035720 intraciliary anterograde transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Anterograde IFT (ISS from mouse). Reason: As above. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0035869 ciliary transition zone | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: ciliary transition zone (Supported). Reason: Consistent with TULP3 entering cilia with IFT-A through the ciliary base; image not inspected. Supporting Evidence: PMID:28154160 We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane. |
| GO:0042149 cellular response to glucose starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to glucose starvation transferred from mouse. Reason: Mouse data link TULP3 to calorie-restriction/AMPK responses; not examined in human and peripheral to ciliary trafficking. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
| GO:0042149 cellular response to glucose starvation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to glucose starvation (ISS from mouse). Reason: As above. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
| GO:0044877 protein-containing complex binding | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | MODIFY | Summary: TULP3 binds the IFT-A complex. Reason: The complex bound is IFT-A; the specific term intraciliary transport particle A binding is more informative. Proposed replacements: intraciliary transport particle A binding Supporting Evidence: PMID:20889716 We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. |
| GO:0045879 negative regulation of smoothened signaling pathway | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 negatively regulates Hedgehog signalling in the mouse embryo. Reason: Well established: TULP3 imports GPR161 (a Hh repressor) into cilia; loss ventralizes the neural tube. Supporting Evidence: PMID:20889716 TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3-IFT-A interaction suggests how these proteins cooperate during neural tube patterning. |
| GO:0045879 negative regulation of smoothened signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of smoothened signalling transferred from mouse. Reason: As above. Supporting Evidence: PMID:20889716 TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3-IFT-A interaction suggests how these proteins cooperate during neural tube patterning. |
| GO:0061512 protein localization to cilium | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: protein localization to cilium (tubby family). Reason: Core process. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0061512 protein localization to cilium | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: TULP3 is required for ciliary trafficking of diverse membrane cargo. Reason: Core process. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. PMID:28154160 We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane. |
| GO:0061512 protein localization to cilium | IGI PMID:27727273 Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium... | ACCEPT | Summary: Zfp423-Tulp3 genetic interaction affects ciliary protein localization. Reason: Supports a role of Tulp3 dosage in ciliary protein localization (mouse cerebellar precursors). Supporting Evidence: PMID:27727273 Tulp3 is a direct binding target of Zfp423 and reducing the overexpression of Tulp3 in Zfp423-deficient cells suppresses Smoothened translocation defects. |
| GO:0061512 protein localization to cilium | IMP PMID:27727273 Zfp423 Regulates Sonic Hedgehog Signaling via Primary Cilium... | ACCEPT | Summary: Tulp3 overexpression perturbs Smoothened ciliary translocation. Reason: As above. Supporting Evidence: PMID:27727273 Tulp3 is a direct binding target of Zfp423 and reducing the overexpression of Tulp3 in Zfp423-deficient cells suppresses Smoothened translocation defects. |
| GO:0061512 protein localization to cilium | IMP PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: TULP3 loss blocks ciliary localization of GPCR/polycystin cargo. Reason: Core process. Supporting Evidence: PMID:28154160 In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. |
| GO:0097499 protein localization to non-motile cilium | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3/IFT-A promote GPCR trafficking into primary cilia. Reason: Core process (primary cilia are non-motile). 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:0097499 protein localization to non-motile cilium | IDA PMID:36775821 Human IFT-A complex structures provide molecular insights in... | ACCEPT | Summary: TULP3-IFT-A interface mutants disrupt cargo transport to primary cilia. Reason: Core process. 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 | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation from mouse. Reason: Consistent with experimental data. 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:0097546 ciliary base | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 at the ciliary base. Reason: Consistent with entry through the ciliary base. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0097731 9+0 non-motile cilium | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 in primary (9+0 non-motile) cilia. Reason: Direct localization. Supporting Evidence: PMID:20889716 IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. |
| GO:0120160 intraciliary transport particle A binding | IDA PMID:20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositid... | ACCEPT | Summary: TULP3 binds IFT-A. Reason: Core binding underlying the adaptor role. Supporting Evidence: PMID:20889716 We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. |
| GO:0120160 intraciliary transport particle A binding | IDA PMID:27932497 Intraflagellar transport-A complex mediates ciliary entry an... | ACCEPT | Summary: VIP assays map TULP3 within IFT-A architecture. Reason: Supports direct IFT-A association. Supporting Evidence: PMID:27932497 In this study, we applied the VIP assay to delineate the overall architecture of the mammalian IFT-A complex, including TULP3. |
| GO:0120160 intraciliary transport particle A binding | IDA PMID:28154160 Tubby family proteins are adapters for ciliary trafficking o... | ACCEPT | Summary: IFT-A binding to the TULP3 N terminus. Reason: Supports direct IFT-A association. Supporting Evidence: PMID:28154160 We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane. |
| GO:1902121 lithocholic acid binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lithocholic acid binding transferred from mouse. Reason: Reported for mouse TULP3 in a calorie-restriction/AMPK context; not tested for human TULP3 and independent of the ciliary function. Retained pending replication. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
| GO:1902121 lithocholic acid binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Lithocholic acid binding (ISS from mouse). Reason: As above. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
| GO:1904262 negative regulation of TORC1 signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of TORC1 signalling transferred from mouse. Reason: Part of the mouse lithocholic acid-SIRT1-V-ATPase-AMPK model; peripheral and not human-validated. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
| GO:1904262 negative regulation of TORC1 signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of TORC1 signalling (ISS from mouse). Reason: As above. Supporting Evidence: file:human/TULP3/TULP3-uniprot.txt to calorie restriction: binds lithocholic acid, a metabolite generated |
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Download this section (compressed HTML)Q: How is cargo released from TULP3 inside cilia: is PI(4,5)P2 depletion by INPP5E sufficient, or are additional factors required?
Q: Which tubby-domain surface recognizes cargo ciliary-localization sequences, and do patient variants (e.g., R382W) act by impairing cargo recognition rather than lipid binding?
Q: Are the mouse lithocholic acid/SIRT1/AMPK functions of TULP3 conserved in human cells, and do they relate to its ciliary role?
Q: Does nuclear TULP3 have any transcriptional function, or is nuclear translocation simply a consequence of PI(4,5)P2 loss?
Experiment: Acutely raise ciliary PI(4,5)P2 (cilium-targeted PIP5K or INPP5E inhibition) and track single-molecule TULP3-GPR161 complexes entering and dissociating in human RPE1 cilia.
Hypothesis: Ciliary cargo release by TULP3 requires PI(4,5)P2 depletion in the ciliary membrane.
Type: Live-cell imaging with chemically induced lipid manipulation
Experiment: Rescue TULP3-null patient-derived cells with IFT-A-binding or PI(4,5)P2-binding mutants and measure ciliary cargo and fibrotic gene expression.
Hypothesis: Fibrosis in TULP3-deficient patients reflects loss of ciliary cargo delivery rather than sirtuin regulation.
Type: Separation-of-function rescue
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