{"gene":"TULP3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2010,"finding":"TULP3 binds directly to the IFT-A complex and requires both this interaction and membrane phosphoinositide-binding properties of its tubby domain to promote trafficking of a subset of GPCRs (but not Smoothened) into primary cilia.","method":"Co-immunoprecipitation, phosphoinositide-binding assays, ciliary localization experiments in cells, genetic analysis in mouse embryos","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phosphoinositide binding assays, mutagenesis, and in vivo genetic epistasis; replicated across multiple subsequent studies","pmids":["20889716"],"is_preprint":false},{"year":2010,"finding":"TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3-IFT-A interaction underlies their cooperative function during neural tube patterning.","method":"Genetic epistasis in mouse embryos (compound mutants), ciliary localization experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple allele combinations, replicated across at least three independent mouse studies","pmids":["20889716","19286674","19223390","19334287"],"is_preprint":false},{"year":2009,"finding":"Genetic epistasis shows that TULP3 acts downstream of Shh and Smoothened but upstream of Gli2 and requires Kif3A (IFT/ciliogenesis) to negatively regulate Hedgehog signaling in the neural tube.","method":"Genetic epistasis in mouse embryos (Tulp3/Shh, Tulp3/Smo, Tulp3/Kif3A compound mutants)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple compound-mutant epistasis experiments, replicated by two independent labs in the same year","pmids":["19286674","19223390"],"is_preprint":false},{"year":2009,"finding":"TULP3 localizes to the tips of primary cilia, suggesting a cilium-based mechanism for its regulation of the Hedgehog pathway.","method":"Immunofluorescence microscopy of primary cilia in mouse embryonic tissues","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunofluorescence, reported by two independent labs but without functional mutagenesis in the same papers","pmids":["19286674","19223390"],"is_preprint":false},{"year":2001,"finding":"Germline knockout of Tulp3 in mice causes failure of neural tube closure and increased neuroepithelial apoptosis specifically in the hindbrain and caudal neural tube, establishing TULP3 as essential for embryonic neural development.","method":"Homologous recombination knockout in mice, histology, TUNEL assay, immunostaining","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean germline KO with specific cellular phenotype (apoptosis in defined region), foundational loss-of-function study","pmids":["11406614"],"is_preprint":false},{"year":2019,"finding":"TULP3 is required for ciliary trafficking of polycystin-1, polycystin-2, and the small GTPase ARL13B in kidney collecting duct cells without affecting cilia structure, and Tulp3 nephron-specific knockout mice develop cystic kidneys with elevated MAPK/ERK, mTOR, and cAMP signaling.","method":"Nephron-specific conditional Tulp3 knockout in mice, immunofluorescence, Western blot, cAMP assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined ciliary cargo readouts and signaling pathway changes, replicated by independent lab same year","pmids":["30799239","30799240"],"is_preprint":false},{"year":2019,"finding":"TULP3 is required for ciliary localization of Arl13b in kidney cilia, and concomitant loss of Tulp3 in an adult inducible Pkd1-deletion ADPKD model surprisingly ameliorates cystic disease.","method":"Forward genetic screen in mouse, hypomorphic Tulp3 missense allele, conditional double knockouts (Tulp3/Pkd1), immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis and conditional double-KO experiments, replicated by independent lab same year","pmids":["30799240","30799239"],"is_preprint":false},{"year":2018,"finding":"TULP3 is required for ciliary localization of membrane-associated proteins ARL13B and INPP5E; this requires TULP3's ability to bind the IFT-A complex, as an IFT-A-binding-deficient TULP3 mutant fails to rescue localization in TULP3-KO cells.","method":"CRISPR/Cas9 knockout of TULP3 in RPE-1 cells, immunofluorescence, rescue with wild-type vs. mutant TULP3","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO, domain-specific rescue experiments, two orthogonal readouts (ARL13B and INPP5E), single lab","pmids":["30583862"],"is_preprint":false},{"year":2023,"finding":"TULP3 transports the palmitoylated GTPase ARL13B into cilia through a ciliary localization sequence (CLS); an N-terminal amphipathic helix of ARL13B interacts with the TULP3 tubby domain irrespective of palmitoylation. This transport requires IFT-A binding but not phosphoinositide binding by TULP3, distinguishing it mechanistically from transmembrane cargo transport.","method":"Mutational analysis of ARL13B and TULP3, co-immunoprecipitation, ciliary localization assays in cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structure-guided mutagenesis, domain-specific rescue, multiple orthogonal methods, single lab","pmids":["36652335"],"is_preprint":false},{"year":2024,"finding":"A specific surface region on the β-barrel of the TULP3 tubby domain (overlying β-strands 8–12, away from the phosphoinositide binding site) mediates ciliary trafficking of both lipidated and transmembrane cargoes; residues in this region were identified by proximity biotinylation-MS, structural analysis, and validated by patient TULP3 variants.","method":"Proximity biotinylation-mass spectrometry (BioID), structural analysis, TULP3 variant functional rescue assays in cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proximity proteomics, structural mapping, mutagenesis, and patient variant validation; single lab with multiple orthogonal methods","pmids":["39565681"],"is_preprint":false},{"year":2024,"finding":"LCA-bound TULP3 acts as a receptor for lithocholic acid (LCA) and allosterically activates sirtuins (SIRT1); proteomics identified TULP3 as a SIRT1-interacting protein, and the TULP3-sirtuin interaction is conserved from nematodes (tub-1) to flies (ktub) to mammals.","method":"Co-immunoprecipitation proteomics (SIRT1 pulldown), biochemical binding assays, genetic epistasis in C. elegans and Drosophila","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP proteomics plus in vivo genetic epistasis across multiple model organisms; published in high-impact peer-reviewed journal","pmids":["39695235"],"is_preprint":false},{"year":2022,"finding":"TULP3 interacts with the nuclear deacetylase SIRT1; disruption of TULP3 in patient-derived primary cells results in increased DNA damage ex vivo, suggesting a role in DNA damage repair.","method":"Co-immunoprecipitation, DNA damage assay in patient-derived primary cells, transcriptomics","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and cell-based assay in single study; interaction later corroborated by Qu et al. 2024 but full mechanism not established here","pmids":["35397207"],"is_preprint":false},{"year":2022,"finding":"The TULP3 R382W patient missense variant, located in the tubby domain at the phosphoinositide binding interface, severely reduces ciliary localization of ARL13B, INPP5E, and GPR161, establishing Arg382 as a critical residue for tubby domain-mediated phosphoinositide binding and cargo trafficking.","method":"Expression of patient variant in IMCD-3 cells, immunofluorescence for ciliary cargo localization","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean cell-based functional assay with multiple cargoes, single lab, single method per cargo","pmids":["36276950"],"is_preprint":false},{"year":2025,"finding":"TULP3 physically associates with ACE2 and facilitates ACE2 localization to the primary cilium; TULP3 depletion removes ACE2 from ciliary axonemes and impairs SARS-CoV-2 pseudovirus entry. This ciliary ACE2 targeting is partially dependent on TULP3's IFT-A interaction.","method":"Co-immunoprecipitation, immunofluorescence/confocal microscopy, TULP3 knockdown, SARS-CoV-2 pseudovirus infection assays, IFT-A-binding-deficient TULP3 mutant rescue","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus functional pseudovirus assay and mutant rescue, single lab, single study","pmids":["41316318"],"is_preprint":false},{"year":2024,"finding":"Both the N-terminal and C-terminal domains of TULP3 are necessary for interaction with SIRT1 and SIRT2; TULP3 is not a deacetylation substrate for SIRT1.","method":"Biochemical and biophysical interaction assays (domain deletion constructs), in vitro deacetylation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays with domain mapping and negative deacetylation result; preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2024.12.23.630205"],"is_preprint":true},{"year":2023,"finding":"TULP3 localizes to kinocilia of cochlear and vestibular hair cells during early postnatal development but is subsequently lost before the onset of hearing, while later appearing at microtubule bundles in non-sensory Pillar and Deiters cells, suggesting context-dependent ciliary and cytoskeletal roles.","method":"Immunofluorescence microscopy with spatiotemporal analysis in mouse inner ear","journal":"Frontiers in neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunofluorescence only, no functional consequence established, single lab","pmids":["37144094"],"is_preprint":false}],"current_model":"TULP3 is a ciliary trafficking adaptor that bridges the IFT-A complex (via its N-terminal region) and membrane phosphoinositides (via the tubby domain β-barrel) to transport diverse cargoes—including GPCRs, polycystins, ARL13B, INPP5E, and ACE2—into primary cilia, thereby negatively regulating Hedgehog/Smoothened signaling downstream of SMO and upstream of Gli2/Gli3 and controlling cystogenesis; additionally, LCA-bound TULP3 allosterically activates sirtuins (SIRT1/SIRT2), coupling nutrient sensing to AMPK activation via v-ATPase deacetylation."},"narrative":{"mechanistic_narrative":"TULP3 is a ciliary trafficking adaptor that delivers a diverse set of membrane-associated and transmembrane cargoes into primary cilia, where it functions as a negative regulator of Hedgehog signaling and a controller of renal cystogenesis [PMID:20889716, PMID:19286674, PMID:19223390, PMID:19334287, PMID:30799239, PMID:30799240]. It operates by simultaneously engaging the intraflagellar transport IFT-A complex through its N-terminal region and membrane phosphoinositides through the β-barrel of its tubby domain, two binding activities both required to ferry a subset of GPCRs into cilia [PMID:20889716]. Genetic epistasis in mouse embryos places TULP3 and IFT-A downstream of Shh and Smoothened but upstream of Gli2, with cilium-based action depending on Kif3A/IFT, thereby restraining Hedgehog output during neural tube patterning; loss of Tulp3 causes failed neural tube closure and hindbrain/caudal neuroepithelial apoptosis [PMID:20889716, PMID:19286674, PMID:19223390, PMID:19334287, PMID:11406614]. Distinct cargoes use distinct rules: ciliary import of the palmitoylated GTPase ARL13B and of INPP5E requires the IFT-A interaction, with ARL13B engaging the tubby domain via an N-terminal amphipathic helix independent of phosphoinositide binding, whereas transmembrane cargo import additionally needs phosphoinositide binding [PMID:30583862, PMID:36652335]. A surface on the tubby β-barrel overlying strands 8–12, separate from the phosphoinositide site, mediates trafficking of both lipidated and transmembrane cargoes and is disrupted by patient variants [PMID:39565681]. In the kidney, TULP3 traffics polycystin-1, polycystin-2 and ARL13B, and its loss produces cystic kidneys with elevated MAPK/ERK, mTOR and cAMP signaling, yet concomitant Tulp3 loss paradoxically ameliorates Pkd1-driven cystic disease [PMID:30799239, PMID:30799240]. Beyond cilia, TULP3 binds the sirtuins SIRT1 and SIRT2 through both its N- and C-terminal domains and, when bound to lithocholic acid, allosterically activates SIRT1, a TULP3–sirtuin interaction conserved from nematodes to mammals [PMID:39695235]. TULP3 also associates with ACE2 to target it to the ciliary axoneme, supporting SARS-CoV-2 pseudovirus entry [PMID:41316318].","teleology":[{"year":2001,"claim":"Established that TULP3 is essential for mammalian neural development before any molecular mechanism was known, defining a loss-of-function phenotype to be explained.","evidence":"Germline Tulp3 knockout in mice with histology and TUNEL","pmids":["11406614"],"confidence":"High","gaps":["Did not identify molecular partners or pathway","Did not link phenotype to cilia"]},{"year":2009,"claim":"Resolved where in the Hedgehog cascade TULP3 acts and tied its function to cilia, showing it works downstream of Smoothened, upstream of Gli2, and requires Kif3A/IFT.","evidence":"Compound-mutant genetic epistasis in mouse embryos plus ciliary tip immunofluorescence","pmids":["19286674","19223390"],"confidence":"High","gaps":["Did not define the biochemical adaptor activity","Ciliary localization shown without functional mutagenesis in the same work"]},{"year":2010,"claim":"Defined the bipartite molecular mechanism: TULP3 bridges IFT-A and membrane phosphoinositides to import a subset of GPCRs and, together with IFT-A, negatively regulates Hedgehog signaling.","evidence":"Reciprocal Co-IP, phosphoinositide-binding assays, ciliary localization, and mouse genetic epistasis","pmids":["20889716","19286674","19223390","19334287"],"confidence":"High","gaps":["Smoothened itself was not a TULP3 cargo, leaving how SMO output is restrained unresolved","Full cargo repertoire unknown"]},{"year":2018,"claim":"Extended the cargo set to membrane-associated ARL13B and INPP5E and showed the IFT-A interaction is required, using domain-specific rescue in human knockout cells.","evidence":"CRISPR TULP3 knockout in RPE-1 cells with wild-type vs IFT-A-binding-deficient rescue and immunofluorescence","pmids":["30583862"],"confidence":"High","gaps":["Did not separate phosphoinositide vs IFT-A requirements per cargo","Single lab"]},{"year":2019,"claim":"Translated the trafficking mechanism into disease relevance by showing TULP3 imports polycystins and ARL13B in kidney and that its loss drives cystogenesis, while paradoxically rescuing Pkd1-driven disease.","evidence":"Nephron-specific and inducible conditional Tulp3 knockouts, Tulp3/Pkd1 double knockouts, immunofluorescence, signaling and cAMP assays","pmids":["30799239","30799240"],"confidence":"High","gaps":["Mechanism of the paradoxical Pkd1-cyst amelioration not explained","Causal link between specific cargo loss and signaling changes not dissected"]},{"year":2023,"claim":"Distinguished lipidated from transmembrane cargo transport mechanistically, showing ARL13B uses a CLS/amphipathic helix binding the tubby domain and requires IFT-A but not phosphoinositide binding.","evidence":"Structure-guided mutagenesis of ARL13B and TULP3, Co-IP, and ciliary localization assays","pmids":["36652335"],"confidence":"High","gaps":["Single lab","Generalization across other lipidated cargoes not established"]},{"year":2024,"claim":"Mapped a discrete tubby β-barrel surface (strands 8–12) distinct from the phosphoinositide site that handles both cargo classes, validated by patient variants.","evidence":"Proximity biotinylation-MS, structural analysis, and TULP3 variant rescue assays","pmids":["39565681"],"confidence":"High","gaps":["Atomic-resolution cargo-bound structure not reported","Single lab"]},{"year":2024,"claim":"Revealed a cilium-independent role: lithocholic-acid-bound TULP3 binds and allosterically activates sirtuins, a conserved nutrient-sensing function.","evidence":"SIRT1 pulldown proteomics, biochemical binding assays, and genetic epistasis in C. elegans and Drosophila","pmids":["39695235"],"confidence":"High","gaps":["Structural basis of allosteric activation not defined","Relationship to ciliary trafficking role unresolved"]},{"year":2024,"claim":"Mapped the TULP3–sirtuin interface to both terminal domains and showed TULP3 is not itself a deacetylation substrate.","evidence":"Domain-deletion biochemical binding and in vitro deacetylation assays (preprint)","pmids":["bio_10.1101_2024.12.23.630205"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Functional consequence of the domain requirements in cells not shown"]},{"year":2022,"claim":"Linked TULP3 to SIRT1 and to genome stability, finding increased DNA damage upon disruption in patient cells.","evidence":"Co-IP, DNA damage assay in patient-derived primary cells, transcriptomics","pmids":["35397207"],"confidence":"Medium","gaps":["Mechanism connecting TULP3 to DNA repair not established","Single study"]},{"year":2025,"claim":"Added ACE2 as a TULP3 cargo and connected ciliary ACE2 targeting to viral entry.","evidence":"Co-IP, confocal microscopy, knockdown, IFT-A-mutant rescue, and SARS-CoV-2 pseudovirus assays","pmids":["41316318"],"confidence":"Medium","gaps":["Single lab/study","Physiological role of ciliary ACE2 beyond viral entry unclear"]},{"year":null,"claim":"How TULP3 reconciles its ciliary trafficking function with its cytoplasmic/nuclear sirtuin-activating role, and how the paradoxical effects on Pkd1 cystogenesis arise, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model spanning ciliary and sirtuin functions","No structure of TULP3 bound to cargo or to sirtuins"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,8,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,5,7,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,13]}],"complexes":["IFT-A"],"partners":["IFT-A","ARL13B","INPP5E","GPR161","SIRT1","SIRT2","ACE2","PKD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75386","full_name":"Tubby-related protein 3","aliases":["Tubby-like protein 3"],"length_aa":442,"mass_kda":49.6,"function":"Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein-coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh signaling. Binds to phosphorylated inositide (phosphoinositide) lipids. Both IFT-A- and phosphoinositide-binding properties are required to regulate ciliary G protein-coupled receptor trafficking. During adipogenesis, regulates ciliary trafficking of FFAR4 in preadipocytes","subcellular_location":"Nucleus; Cell membrane; Cell projection, cilium; Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/O75386/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TULP3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD54","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TULP3","total_profiled":1310},"omim":[{"mim_id":"619902","title":"HEPATORENOCARDIAC DEGENERATIVE FIBROSIS; HRCDF","url":"https://www.omim.org/entry/619902"},{"mim_id":"612250","title":"G PROTEIN-COUPLED RECEPTOR 161: GPR161","url":"https://www.omim.org/entry/612250"},{"mim_id":"604730","title":"TUB-LIKE PROTEIN 3; TULP3","url":"https://www.omim.org/entry/604730"},{"mim_id":"604114","title":"PHOSPHOLIPASE C, BETA-2; PLCB2","url":"https://www.omim.org/entry/604114"},{"mim_id":"601197","title":"TUB BIPARTITE TRANSCRIPTION FACTOR; TUB","url":"https://www.omim.org/entry/601197"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Primary cilium","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium transition zone","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TULP3"},"hgnc":{"alias_symbol":["TUBL3"],"prev_symbol":[]},"alphafold":{"accession":"O75386","domains":[{"cath_id":"3.20.90.10","chopping":"178-291_298-442","consensus_level":"medium","plddt":89.1896,"start":178,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75386","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75386-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75386-F1-predicted_aligned_error_v6.png","plddt_mean":72.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TULP3","jax_strain_url":"https://www.jax.org/strain/search?query=TULP3"},"sequence":{"accession":"O75386","fasta_url":"https://rest.uniprot.org/uniprotkb/O75386.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75386/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75386"}},"corpus_meta":[{"pmid":"20889716","id":"PMC_20889716","title":"TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia.","date":"2010","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/20889716","citation_count":360,"is_preprint":false},{"pmid":"19286674","id":"PMC_19286674","title":"Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19286674","citation_count":97,"is_preprint":false},{"pmid":"19223390","id":"PMC_19223390","title":"Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19223390","citation_count":78,"is_preprint":false},{"pmid":"11406614","id":"PMC_11406614","title":"Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11406614","citation_count":63,"is_preprint":false},{"pmid":"39695235","id":"PMC_39695235","title":"Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39695235","citation_count":59,"is_preprint":false},{"pmid":"9828123","id":"PMC_9828123","title":"Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9828123","citation_count":59,"is_preprint":false},{"pmid":"30799240","id":"PMC_30799240","title":"Tulp3 Is a Ciliary Trafficking Gene that Regulates Polycystic Kidney Disease.","date":"2019","source":"Current biology : 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in gastric cancer via the PTEN/Akt/Snail pathway.","date":"2022","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35344762","citation_count":4,"is_preprint":false},{"pmid":"37144094","id":"PMC_37144094","title":"Distribution of ciliary adaptor proteins tubby and TULP3 in the organ of Corti.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37144094","citation_count":1,"is_preprint":false},{"pmid":"41316318","id":"PMC_41316318","title":"Primary cilium and TULP3-dependent ciliary targeting of ACE2 in SARS-CoV-2 tropism.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41316318","citation_count":0,"is_preprint":false},{"pmid":"40940409","id":"PMC_40940409","title":"Tulp3 deficiency results in ciliopathy phenotypes during zebrafish embryogenesis.","date":"2025","source":"Scientific 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40579123","citation_count":0,"is_preprint":false},{"pmid":"41000950","id":"PMC_41000950","title":"Tulp3 quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress Zfp423 mutations in mice.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41000950","citation_count":0,"is_preprint":false},{"pmid":"35510584","id":"PMC_35510584","title":"TULP3 NLS inhibition: an in silico study to hamper cargo transport to nucleus.","date":"2022","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/35510584","citation_count":0,"is_preprint":false},{"pmid":"40066670","id":"PMC_40066670","title":"Ciliopathy due to genetic alterations of TULP3 as an uncommon cause of hepatorenocardiac fibrosis.","date":"2025","source":"Revista espanola de enfermedades digestivas","url":"https://pubmed.ncbi.nlm.nih.gov/40066670","citation_count":0,"is_preprint":false},{"pmid":"40226390","id":"PMC_40226390","title":"Unearthing TULP3 Mutation as a Rare Cause of Cryptogenic Cirrhosis: A Case Report and Review of the Literature.","date":"2025","source":"Journal of clinical and experimental hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40226390","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.25.650726","title":"<i>Tulp3</i>  quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress  <i>Zfp423</i>  mutations in mice","date":"2025-04-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.25.650726","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.23.630205","title":"Deciphering the molecular mechanism associated with the interaction of TULP3 and Histone deacetylases, SIRT1 and SIRT2","date":"2024-12-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.23.630205","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15978,"output_tokens":3633,"usd":0.051215,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11254,"output_tokens":3748,"usd":0.074985,"stage2_stop_reason":"end_turn"},"total_usd":0.1262,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"TULP3 binds directly to the IFT-A complex and requires both this interaction and membrane phosphoinositide-binding properties of its tubby domain to promote trafficking of a subset of GPCRs (but not Smoothened) into primary cilia.\",\n      \"method\": \"Co-immunoprecipitation, phosphoinositide-binding assays, ciliary localization experiments in cells, genetic analysis in mouse embryos\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phosphoinositide binding assays, mutagenesis, and in vivo genetic epistasis; replicated across multiple subsequent studies\",\n      \"pmids\": [\"20889716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3-IFT-A interaction underlies their cooperative function during neural tube patterning.\",\n      \"method\": \"Genetic epistasis in mouse embryos (compound mutants), ciliary localization experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple allele combinations, replicated across at least three independent mouse studies\",\n      \"pmids\": [\"20889716\", \"19286674\", \"19223390\", \"19334287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Genetic epistasis shows that TULP3 acts downstream of Shh and Smoothened but upstream of Gli2 and requires Kif3A (IFT/ciliogenesis) to negatively regulate Hedgehog signaling in the neural tube.\",\n      \"method\": \"Genetic epistasis in mouse embryos (Tulp3/Shh, Tulp3/Smo, Tulp3/Kif3A compound mutants)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple compound-mutant epistasis experiments, replicated by two independent labs in the same year\",\n      \"pmids\": [\"19286674\", \"19223390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TULP3 localizes to the tips of primary cilia, suggesting a cilium-based mechanism for its regulation of the Hedgehog pathway.\",\n      \"method\": \"Immunofluorescence microscopy of primary cilia in mouse embryonic tissues\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunofluorescence, reported by two independent labs but without functional mutagenesis in the same papers\",\n      \"pmids\": [\"19286674\", \"19223390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Germline knockout of Tulp3 in mice causes failure of neural tube closure and increased neuroepithelial apoptosis specifically in the hindbrain and caudal neural tube, establishing TULP3 as essential for embryonic neural development.\",\n      \"method\": \"Homologous recombination knockout in mice, histology, TUNEL assay, immunostaining\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean germline KO with specific cellular phenotype (apoptosis in defined region), foundational loss-of-function study\",\n      \"pmids\": [\"11406614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TULP3 is required for ciliary trafficking of polycystin-1, polycystin-2, and the small GTPase ARL13B in kidney collecting duct cells without affecting cilia structure, and Tulp3 nephron-specific knockout mice develop cystic kidneys with elevated MAPK/ERK, mTOR, and cAMP signaling.\",\n      \"method\": \"Nephron-specific conditional Tulp3 knockout in mice, immunofluorescence, Western blot, cAMP assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined ciliary cargo readouts and signaling pathway changes, replicated by independent lab same year\",\n      \"pmids\": [\"30799239\", \"30799240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TULP3 is required for ciliary localization of Arl13b in kidney cilia, and concomitant loss of Tulp3 in an adult inducible Pkd1-deletion ADPKD model surprisingly ameliorates cystic disease.\",\n      \"method\": \"Forward genetic screen in mouse, hypomorphic Tulp3 missense allele, conditional double knockouts (Tulp3/Pkd1), immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis and conditional double-KO experiments, replicated by independent lab same year\",\n      \"pmids\": [\"30799240\", \"30799239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TULP3 is required for ciliary localization of membrane-associated proteins ARL13B and INPP5E; this requires TULP3's ability to bind the IFT-A complex, as an IFT-A-binding-deficient TULP3 mutant fails to rescue localization in TULP3-KO cells.\",\n      \"method\": \"CRISPR/Cas9 knockout of TULP3 in RPE-1 cells, immunofluorescence, rescue with wild-type vs. mutant TULP3\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO, domain-specific rescue experiments, two orthogonal readouts (ARL13B and INPP5E), single lab\",\n      \"pmids\": [\"30583862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TULP3 transports the palmitoylated GTPase ARL13B into cilia through a ciliary localization sequence (CLS); an N-terminal amphipathic helix of ARL13B interacts with the TULP3 tubby domain irrespective of palmitoylation. This transport requires IFT-A binding but not phosphoinositide binding by TULP3, distinguishing it mechanistically from transmembrane cargo transport.\",\n      \"method\": \"Mutational analysis of ARL13B and TULP3, co-immunoprecipitation, ciliary localization assays in cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-guided mutagenesis, domain-specific rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36652335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A specific surface region on the β-barrel of the TULP3 tubby domain (overlying β-strands 8–12, away from the phosphoinositide binding site) mediates ciliary trafficking of both lipidated and transmembrane cargoes; residues in this region were identified by proximity biotinylation-MS, structural analysis, and validated by patient TULP3 variants.\",\n      \"method\": \"Proximity biotinylation-mass spectrometry (BioID), structural analysis, TULP3 variant functional rescue assays in cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proximity proteomics, structural mapping, mutagenesis, and patient variant validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39565681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LCA-bound TULP3 acts as a receptor for lithocholic acid (LCA) and allosterically activates sirtuins (SIRT1); proteomics identified TULP3 as a SIRT1-interacting protein, and the TULP3-sirtuin interaction is conserved from nematodes (tub-1) to flies (ktub) to mammals.\",\n      \"method\": \"Co-immunoprecipitation proteomics (SIRT1 pulldown), biochemical binding assays, genetic epistasis in C. elegans and Drosophila\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP proteomics plus in vivo genetic epistasis across multiple model organisms; published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"39695235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TULP3 interacts with the nuclear deacetylase SIRT1; disruption of TULP3 in patient-derived primary cells results in increased DNA damage ex vivo, suggesting a role in DNA damage repair.\",\n      \"method\": \"Co-immunoprecipitation, DNA damage assay in patient-derived primary cells, transcriptomics\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and cell-based assay in single study; interaction later corroborated by Qu et al. 2024 but full mechanism not established here\",\n      \"pmids\": [\"35397207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The TULP3 R382W patient missense variant, located in the tubby domain at the phosphoinositide binding interface, severely reduces ciliary localization of ARL13B, INPP5E, and GPR161, establishing Arg382 as a critical residue for tubby domain-mediated phosphoinositide binding and cargo trafficking.\",\n      \"method\": \"Expression of patient variant in IMCD-3 cells, immunofluorescence for ciliary cargo localization\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean cell-based functional assay with multiple cargoes, single lab, single method per cargo\",\n      \"pmids\": [\"36276950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TULP3 physically associates with ACE2 and facilitates ACE2 localization to the primary cilium; TULP3 depletion removes ACE2 from ciliary axonemes and impairs SARS-CoV-2 pseudovirus entry. This ciliary ACE2 targeting is partially dependent on TULP3's IFT-A interaction.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/confocal microscopy, TULP3 knockdown, SARS-CoV-2 pseudovirus infection assays, IFT-A-binding-deficient TULP3 mutant rescue\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus functional pseudovirus assay and mutant rescue, single lab, single study\",\n      \"pmids\": [\"41316318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Both the N-terminal and C-terminal domains of TULP3 are necessary for interaction with SIRT1 and SIRT2; TULP3 is not a deacetylation substrate for SIRT1.\",\n      \"method\": \"Biochemical and biophysical interaction assays (domain deletion constructs), in vitro deacetylation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays with domain mapping and negative deacetylation result; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.23.630205\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TULP3 localizes to kinocilia of cochlear and vestibular hair cells during early postnatal development but is subsequently lost before the onset of hearing, while later appearing at microtubule bundles in non-sensory Pillar and Deiters cells, suggesting context-dependent ciliary and cytoskeletal roles.\",\n      \"method\": \"Immunofluorescence microscopy with spatiotemporal analysis in mouse inner ear\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunofluorescence only, no functional consequence established, single lab\",\n      \"pmids\": [\"37144094\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TULP3 is a ciliary trafficking adaptor that bridges the IFT-A complex (via its N-terminal region) and membrane phosphoinositides (via the tubby domain β-barrel) to transport diverse cargoes—including GPCRs, polycystins, ARL13B, INPP5E, and ACE2—into primary cilia, thereby negatively regulating Hedgehog/Smoothened signaling downstream of SMO and upstream of Gli2/Gli3 and controlling cystogenesis; additionally, LCA-bound TULP3 allosterically activates sirtuins (SIRT1/SIRT2), coupling nutrient sensing to AMPK activation via v-ATPase deacetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TULP3 is a ciliary trafficking adaptor that delivers a diverse set of membrane-associated and transmembrane cargoes into primary cilia, where it functions as a negative regulator of Hedgehog signaling and a controller of renal cystogenesis [#0, #1, #5]. It operates by simultaneously engaging the intraflagellar transport IFT-A complex through its N-terminal region and membrane phosphoinositides through the β-barrel of its tubby domain, two binding activities both required to ferry a subset of GPCRs into cilia [#0]. Genetic epistasis in mouse embryos places TULP3 and IFT-A downstream of Shh and Smoothened but upstream of Gli2, with cilium-based action depending on Kif3A/IFT, thereby restraining Hedgehog output during neural tube patterning; loss of Tulp3 causes failed neural tube closure and hindbrain/caudal neuroepithelial apoptosis [#1, #2, #4]. Distinct cargoes use distinct rules: ciliary import of the palmitoylated GTPase ARL13B and of INPP5E requires the IFT-A interaction, with ARL13B engaging the tubby domain via an N-terminal amphipathic helix independent of phosphoinositide binding, whereas transmembrane cargo import additionally needs phosphoinositide binding [#7, #8]. A surface on the tubby β-barrel overlying strands 8–12, separate from the phosphoinositide site, mediates trafficking of both lipidated and transmembrane cargoes and is disrupted by patient variants [#9]. In the kidney, TULP3 traffics polycystin-1, polycystin-2 and ARL13B, and its loss produces cystic kidneys with elevated MAPK/ERK, mTOR and cAMP signaling, yet concomitant Tulp3 loss paradoxically ameliorates Pkd1-driven cystic disease [#5, #6]. Beyond cilia, TULP3 binds the sirtuins SIRT1 and SIRT2 through both its N- and C-terminal domains and, when bound to lithocholic acid, allosterically activates SIRT1, a TULP3–sirtuin interaction conserved from nematodes to mammals [#10]. TULP3 also associates with ACE2 to target it to the ciliary axoneme, supporting SARS-CoV-2 pseudovirus entry [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that TULP3 is essential for mammalian neural development before any molecular mechanism was known, defining a loss-of-function phenotype to be explained.\",\n      \"evidence\": \"Germline Tulp3 knockout in mice with histology and TUNEL\",\n      \"pmids\": [\"11406614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify molecular partners or pathway\", \"Did not link phenotype to cilia\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved where in the Hedgehog cascade TULP3 acts and tied its function to cilia, showing it works downstream of Smoothened, upstream of Gli2, and requires Kif3A/IFT.\",\n      \"evidence\": \"Compound-mutant genetic epistasis in mouse embryos plus ciliary tip immunofluorescence\",\n      \"pmids\": [\"19286674\", \"19223390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical adaptor activity\", \"Ciliary localization shown without functional mutagenesis in the same work\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the bipartite molecular mechanism: TULP3 bridges IFT-A and membrane phosphoinositides to import a subset of GPCRs and, together with IFT-A, negatively regulates Hedgehog signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, phosphoinositide-binding assays, ciliary localization, and mouse genetic epistasis\",\n      \"pmids\": [\"20889716\", \"19286674\", \"19223390\", \"19334287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Smoothened itself was not a TULP3 cargo, leaving how SMO output is restrained unresolved\", \"Full cargo repertoire unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the cargo set to membrane-associated ARL13B and INPP5E and showed the IFT-A interaction is required, using domain-specific rescue in human knockout cells.\",\n      \"evidence\": \"CRISPR TULP3 knockout in RPE-1 cells with wild-type vs IFT-A-binding-deficient rescue and immunofluorescence\",\n      \"pmids\": [\"30583862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate phosphoinositide vs IFT-A requirements per cargo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Translated the trafficking mechanism into disease relevance by showing TULP3 imports polycystins and ARL13B in kidney and that its loss drives cystogenesis, while paradoxically rescuing Pkd1-driven disease.\",\n      \"evidence\": \"Nephron-specific and inducible conditional Tulp3 knockouts, Tulp3/Pkd1 double knockouts, immunofluorescence, signaling and cAMP assays\",\n      \"pmids\": [\"30799239\", \"30799240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the paradoxical Pkd1-cyst amelioration not explained\", \"Causal link between specific cargo loss and signaling changes not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished lipidated from transmembrane cargo transport mechanistically, showing ARL13B uses a CLS/amphipathic helix binding the tubby domain and requires IFT-A but not phosphoinositide binding.\",\n      \"evidence\": \"Structure-guided mutagenesis of ARL13B and TULP3, Co-IP, and ciliary localization assays\",\n      \"pmids\": [\"36652335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Generalization across other lipidated cargoes not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a discrete tubby β-barrel surface (strands 8–12) distinct from the phosphoinositide site that handles both cargo classes, validated by patient variants.\",\n      \"evidence\": \"Proximity biotinylation-MS, structural analysis, and TULP3 variant rescue assays\",\n      \"pmids\": [\"39565681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution cargo-bound structure not reported\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a cilium-independent role: lithocholic-acid-bound TULP3 binds and allosterically activates sirtuins, a conserved nutrient-sensing function.\",\n      \"evidence\": \"SIRT1 pulldown proteomics, biochemical binding assays, and genetic epistasis in C. elegans and Drosophila\",\n      \"pmids\": [\"39695235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of allosteric activation not defined\", \"Relationship to ciliary trafficking role unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the TULP3–sirtuin interface to both terminal domains and showed TULP3 is not itself a deacetylation substrate.\",\n      \"evidence\": \"Domain-deletion biochemical binding and in vitro deacetylation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.23.630205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Functional consequence of the domain requirements in cells not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked TULP3 to SIRT1 and to genome stability, finding increased DNA damage upon disruption in patient cells.\",\n      \"evidence\": \"Co-IP, DNA damage assay in patient-derived primary cells, transcriptomics\",\n      \"pmids\": [\"35397207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting TULP3 to DNA repair not established\", \"Single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added ACE2 as a TULP3 cargo and connected ciliary ACE2 targeting to viral entry.\",\n      \"evidence\": \"Co-IP, confocal microscopy, knockdown, IFT-A-mutant rescue, and SARS-CoV-2 pseudovirus assays\",\n      \"pmids\": [\"41316318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab/study\", \"Physiological role of ciliary ACE2 beyond viral entry unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TULP3 reconciles its ciliary trafficking function with its cytoplasmic/nuclear sirtuin-activating role, and how the paradoxical effects on Pkd1 cystogenesis arise, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model spanning ciliary and sirtuin functions\", \"No structure of TULP3 bound to cargo or to sirtuins\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 8, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 5, 7, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 13]}\n    ],\n    \"complexes\": [\"IFT-A\"],\n    \"partners\": [\"IFT-A\", \"ARL13B\", \"INPP5E\", \"GPR161\", \"SIRT1\", \"SIRT2\", \"ACE2\", \"PKD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}