Affinage

TULP3

Tubby-related protein 3 · UniProt O75386

Length
442 aa
Mass
49.6 kDa
Annotated
2026-06-10
27 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    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

    PMID:11406614

    Open questions at the time
    • Did not identify molecular partners or pathway
    • Did not link phenotype to cilia
  2. 2009 High

    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

    PMID:19223390 PMID:19286674

    Open questions at the time
    • Did not define the biochemical adaptor activity
    • Ciliary localization shown without functional mutagenesis in the same work
  3. 2010 High

    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

    PMID:19223390 PMID:19286674 PMID:19334287 PMID:20889716

    Open questions at the time
    • Smoothened itself was not a TULP3 cargo, leaving how SMO output is restrained unresolved
    • Full cargo repertoire unknown
  4. 2018 High

    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

    PMID:30583862

    Open questions at the time
    • Did not separate phosphoinositide vs IFT-A requirements per cargo
    • Single lab
  5. 2019 High

    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

    PMID:30799239 PMID:30799240

    Open questions at the time
    • Mechanism of the paradoxical Pkd1-cyst amelioration not explained
    • Causal link between specific cargo loss and signaling changes not dissected
  6. 2023 High

    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

    PMID:36652335

    Open questions at the time
    • Single lab
    • Generalization across other lipidated cargoes not established
  7. 2024 High

    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

    PMID:39565681

    Open questions at the time
    • Atomic-resolution cargo-bound structure not reported
    • Single lab
  8. 2024 High

    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

    PMID:39695235

    Open questions at the time
    • Structural basis of allosteric activation not defined
    • Relationship to ciliary trafficking role unresolved
  9. 2024 Medium

    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)

    PMID:bio_10.1101_2024.12.23.630205

    Open questions at the time
    • Not yet peer-reviewed
    • Functional consequence of the domain requirements in cells not shown
  10. 2022 Medium

    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

    PMID:35397207

    Open questions at the time
    • Mechanism connecting TULP3 to DNA repair not established
    • Single study
  11. 2025 Medium

    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

    PMID:41316318

    Open questions at the time
    • Single lab/study
    • Physiological role of ciliary ACE2 beyond viral entry unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No integrated model spanning ciliary and sirtuin functions
  • No structure of TULP3 bound to cargo or to sirtuins

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2 R-HSA-1266738 Developmental Biology 1
Partners
ACE2ARL13BGPR161IFT-AINPP5EPKD1SIRT1SIRT2
Complex memberships
IFT-A

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Co-immunoprecipitation, phosphoinositide-binding assays, ciliary localization experiments in cells, genetic analysis in mouse embryos Genes & development High 20889716
2010 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. Genetic epistasis in mouse embryos (compound mutants), ciliary localization experiments Genes & development High 19223390 19286674 19334287 20889716
2009 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. Genetic epistasis in mouse embryos (Tulp3/Shh, Tulp3/Smo, Tulp3/Kif3A compound mutants) Human molecular genetics High 19223390 19286674
2009 TULP3 localizes to the tips of primary cilia, suggesting a cilium-based mechanism for its regulation of the Hedgehog pathway. Immunofluorescence microscopy of primary cilia in mouse embryonic tissues Human molecular genetics Medium 19223390 19286674
2001 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. Homologous recombination knockout in mice, histology, TUNEL assay, immunostaining Human molecular genetics High 11406614
2019 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. Nephron-specific conditional Tulp3 knockout in mice, immunofluorescence, Western blot, cAMP assays Current biology : CB High 30799239 30799240
2019 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. Forward genetic screen in mouse, hypomorphic Tulp3 missense allele, conditional double knockouts (Tulp3/Pkd1), immunofluorescence Current biology : CB High 30799239 30799240
2018 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. CRISPR/Cas9 knockout of TULP3 in RPE-1 cells, immunofluorescence, rescue with wild-type vs. mutant TULP3 Biochemical and biophysical research communications High 30583862
2023 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. Mutational analysis of ARL13B and TULP3, co-immunoprecipitation, ciliary localization assays in cells Molecular biology of the cell High 36652335
2024 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. Proximity biotinylation-mass spectrometry (BioID), structural analysis, TULP3 variant functional rescue assays in cells Molecular biology of the cell High 39565681
2024 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. Co-immunoprecipitation proteomics (SIRT1 pulldown), biochemical binding assays, genetic epistasis in C. elegans and Drosophila Nature High 39695235
2022 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. Co-immunoprecipitation, DNA damage assay in patient-derived primary cells, transcriptomics American journal of human genetics Medium 35397207
2022 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. Expression of patient variant in IMCD-3 cells, immunofluorescence for ciliary cargo localization Frontiers in genetics Medium 36276950
2025 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. Co-immunoprecipitation, immunofluorescence/confocal microscopy, TULP3 knockdown, SARS-CoV-2 pseudovirus infection assays, IFT-A-binding-deficient TULP3 mutant rescue Cell communication and signaling : CCS Medium 41316318
2024 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. Biochemical and biophysical interaction assays (domain deletion constructs), in vitro deacetylation assay bioRxivpreprint Medium bio_10.1101_2024.12.23.630205
2023 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. Immunofluorescence microscopy with spatiotemporal analysis in mouse inner ear Frontiers in neuroscience Low 37144094

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes & development 360 20889716
2009 Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. Human molecular genetics 97 19286674
2009 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. Human molecular genetics 78 19223390
2001 Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice. Human molecular genetics 63 11406614
2024 Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature 59 39695235
1998 Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans. Genomics 59 9828123
2019 Tulp3 Is a Ciliary Trafficking Gene that Regulates Polycystic Kidney Disease. Current biology : CB 58 30799240
2019 Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia. Current biology : CB 52 30799239
2018 TULP3 is required for localization of membrane-associated proteins ARL13B and INPP5E to primary cilia. Biochemical and biophysical research communications 51 30583862
2009 Tulp3 is a critical repressor of mouse hedgehog signaling. Developmental dynamics : an official publication of the American Association of Anatomists 42 19334287
2022 Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. American journal of human genetics 40 35397207
2023 Interactions between TULP3 tubby domain and ARL13B amphipathic helix promote lipidated protein transport to cilia. Molecular biology of the cell 32 36652335
2020 STAT3-induced up-regulation of lncRNA NEAT1 as a ceRNA facilitates abdominal aortic aneurysm formation by elevating TULP3. Bioscience reports 32 31868202
2022 A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease. Frontiers in genetics 13 36276950
2019 TULP3: A potential biomarker in colorectal cancer? PloS one 12 30640939
2024 A defined tubby domain β-barrel surface region of TULP3 mediates ciliary trafficking of diverse cargoes. Molecular biology of the cell 6 39565681
2022 TULP3 silencing suppresses cell proliferation, migration and invasion in gastric cancer via the PTEN/Akt/Snail pathway. Cancer treatment and research communications 4 35344762
2023 Distribution of ciliary adaptor proteins tubby and TULP3 in the organ of Corti. Frontiers in neuroscience 1 37144094
2025 Ciliopathy due to genetic alterations of TULP3 as an uncommon cause of hepatorenocardiac fibrosis. Revista espanola de enfermedades digestivas 0 40066670
2025 Unearthing TULP3 Mutation as a Rare Cause of Cryptogenic Cirrhosis: A Case Report and Review of the Literature. Journal of clinical and experimental hepatology 0 40226390
2025 TULP3 Regulates Proliferation and Differentiation of 3T3-L1 Preadipocytes Through the Hedgehog Signaling Pathway. Biology 0 40282234
2025 Biallelic pathogenic TULP3 variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations. Journal of medical genetics 0 40579123
2025 Tulp3 deficiency results in ciliopathy phenotypes during zebrafish embryogenesis. Scientific reports 0 40940409
2025 Tulp3 quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress Zfp423 mutations in mice. bioRxiv : the preprint server for biology 0 41000950
2025 Tulp3 quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress Zfp423 mutations in mice. PLoS genetics 0 41091799
2025 Primary cilium and TULP3-dependent ciliary targeting of ACE2 in SARS-CoV-2 tropism. Cell communication and signaling : CCS 0 41316318
2022 TULP3 NLS inhibition: an in silico study to hamper cargo transport to nucleus. Journal of biomolecular structure & dynamics 0 35510584

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