Affinage

IFT80

Intraflagellar transport protein 80 homolog · UniProt Q9P2H3

Length
777 aa
Mass
88.0 kDa
Annotated
2026-06-10
21 papers in source corpus 15 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT80 is a component of intraflagellar transport (IFT) complex B that is essential for ciliogenesis and bidirectional transport, with its loss producing shortened or absent cilia and ciliopathy phenotypes including cystic kidneys, photoreceptor outer-segment defects, and opsin mislocalization across zebrafish and Tetrahymena (PMID:17468754, PMID:20207966). Beyond its structural ciliary role, IFT80 acts as an upstream activator of Hedgehog/Gli signaling: hypomorphic cells retain morphologically normal cilia yet fail to activate Hh, and Gli2 overexpression rescues differentiation defects caused by IFT80 loss, establishing IFT80 upstream of Gli2 (PMID:21227999, PMID:22771375, PMID:23333501). Through this cilium-dependent signaling hub, IFT80 governs mesenchymal lineage differentiation and skeletal/dental tissue maintenance, coordinating Hh together with Wnt, TGF-β/Smad2/3, FGF2-FGFR1-PI3K-AKT, TRPA1-Ca2+-AKT/ERK, and TAZ/RUNX2 outputs to drive chondrogenesis, osteogenesis, fracture and socket healing, intervertebral disc maintenance, and odontoblast differentiation (PMID:23333501, PMID:31643106, PMID:31592124, PMID:39954781, PMID:38287672). Distinct from these ciliary functions, IFT80 also acts non-ciliary in osteoclasts, associating with Cbl-b to stabilize it and promote proteasomal degradation of TRAF6, thereby restraining RANKL/NF-κB signaling and osteoclastogenesis (PMID:35733270).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Established IFT80 as an IFT component genuinely required for cilia assembly in vivo, anchoring all later function in ciliary biology.

    Evidence Morpholino knockdown in zebrafish and RNAi in Tetrahymena with ciliary/renal phenotypes

    PMID:17468754

    Open questions at the time
    • Did not resolve which step of IFT (anterograde vs retrograde) IFT80 supports
    • No biochemical placement within complex B
  2. 2010 High

    Defined the tissue consequences of IFT80 loss in sensory cilia and linked it genetically to the BBS module, situating it in a shared ciliary pathway.

    Evidence Zebrafish morpholino knockdown with TEM/IHC of photoreceptors and morpholino co-injection epistasis with bbs4/bbs8

    PMID:20207966

    Open questions at the time
    • Genetic interaction with BBS proteins not validated biochemically
    • Mechanism of opsin transport defect not resolved
  3. 2011 High

    Separated IFT80's signaling role from its structural role by showing Hedgehog activation fails even when cilia remain morphologically intact.

    Evidence Hypomorphic gene-trap mouse embryonic fibroblasts with Hh analog stimulation and cilia morphology readout

    PMID:21227999

    Open questions at the time
    • Molecular step in Hh transduction affected by IFT80 not identified
    • Whether residual IFT80 in hypomorph confounds interpretation
  4. 2012 Medium

    Placed IFT80 upstream of Gli2 in osteogenesis via a functional rescue, converting a correlation into an epistatic order.

    Evidence Lentiviral RNAi in C3H10T1/2 and BMSCs with Gli2 overexpression rescue and SAG treatment

    PMID:22771375

    Open questions at the time
    • Direct biochemical link between IFT80 and Gli2 regulation not shown
    • Single lab, single cell context
  5. 2013 Medium

    Extended the Gli2-upstream role to chondrogenesis and revealed reciprocal Wnt regulation, broadening IFT80's signaling integration.

    Evidence RNAi in mouse BMSCs with Gli2 rescue and chondrogenic differentiation assay

    PMID:23333501

    Open questions at the time
    • Mechanism of Wnt upregulation upon IFT80 loss unexplained
    • No in vivo validation
  6. 2019 Medium

    Demonstrated cilium/IFT80 control of TGF-β/Smad2/3 and FGF2-FGFR1-PI3K-AKT axes in vivo, showing IFT80 coordinates multiple signaling pathways beyond Hh during skeletal and dental development.

    Evidence Conditional KO mice (Col2α1-CreER fracture; odontoblast lineage) plus in vitro chondrocyte and DPSC signaling assays

    PMID:30683845 PMID:31592124 PMID:31643106

    Open questions at the time
    • Whether these pathway effects are all cilium-dependent not dissected
    • Direct molecular partners in TGF-β/FGF signaling not identified
  7. 2020 Medium

    Confirmed IFT80 acts upstream of Hh in intervertebral disc maintenance using pharmacological rescue, generalizing the cilium-Hh axis to additional skeletal tissues.

    Evidence Col2-CreERT and Col1-CreERT conditional KO mice with SAG rescue and expression analysis

    PMID:32227389

    Open questions at the time
    • Cell-type-specific contributions to disc phenotype incompletely separated
    • No biochemical mechanism
  8. 2022 High

    Revealed a cilium-independent function in osteoclasts, where IFT80 binds Cbl-b to drive TRAF6 degradation and restrain RANKL/NF-κB signaling, expanding IFT80's biology beyond transport.

    Evidence Myeloid conditional KO mice, reciprocal Co-IP, ubiquitination assay, and calvarial osteolysis rescue

    PMID:35733270

    Open questions at the time
    • Structural basis of the IFT80-Cbl-b interaction unknown
    • Whether this function shares any machinery with ciliary IFT80 unaddressed
  9. 2022 Medium

    Showed an essential role in early embryonic development with WNT and Hedgehog disruption at the time of zygotic IFT80 activation.

    Evidence CRISPR-Cas9 truncation of IFT80 in bovine embryos with IVF and embryo culture

    PMID:36085107

    Open questions at the time
    • Whether arrest is cilia-dependent at the 8-cell stage unresolved
    • Causal hierarchy between WNT and Hh disruption not established
  10. 2025 Medium

    Identified IFT80 as upstream of a TRPA1-Ca2+-AKT/ERK mechanotransduction axis and a TAZ/RUNX2 osteogenic axis, linking IFT80 to mechanically-driven and healing-associated bone formation.

    Evidence MSC-specific (Prx1Cre) conditional KO mice with mechanical stimulation, Ca2+ imaging, and TRPA1/TAZ overexpression rescue in vivo and in vitro

    PMID:38287672 PMID:39954781

    Open questions at the time
    • Whether TRPA1 and TAZ effects are cilium-dependent not established
    • Direct molecular connection between IFT80 and TRPA1/TAZ regulation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single IFT complex B subunit mechanistically toggles between cilium-based transport/signaling and cilium-independent E3-ligase-adaptor functions, and which interactions are direct, remains unresolved.
  • No structural model of IFT80 within complex B or with Cbl-b
  • Direct substrate/partner contacts for most signaling pathways unidentified
  • Determinants partitioning ciliary vs non-ciliary pools unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 1
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-392499 Metabolism of proteins 1
Partners
CBL-BTRAF6
Complex memberships
IFT complex B

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 IFT80 encodes a component of the intraflagellar transport (IFT) complex; knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia, establishing IFT80 as required for ciliogenesis in vivo. Morpholino knockdown in zebrafish; RNAi knockdown in Tetrahymena thermophila Nature genetics High 17468754
2011 IFT80 is a component of IFT complex B; hypomorphic Ift80 mouse embryonic fibroblasts show significant reduction in Hedgehog pathway activation in response to Hedgehog analog treatment without loss or malformation of cilia, indicating IFT80 has a separable role in Hh signaling beyond ciliogenesis. Gene-trap mouse model (hypomorph); Hedgehog analog stimulation assay in mouse embryonic fibroblasts Human molecular genetics High 21227999
2010 Ift80 knockdown in zebrafish causes defects in photoreceptor outer segment formation, opsin mislocalization in rods and cones, abnormal disc stacking, shortened photoreceptor outer segments, and shorter/reduced kinocilia and motile cilia. Western blot analysis revealed a slight increase in the stability of other IFT proteins upon ift80 loss. Morpholino knockdown in zebrafish; transmission electron microscopy; immunohistochemistry; Western blot Investigative ophthalmology & visual science High 20207966
2010 Co-injection of morpholinos against ift80 and BBS genes (bbs4 or bbs8) led to convergent-extension defects in zebrafish, indicating a genetic interaction between IFT80 and BBS proteins in a shared ciliary pathway. Genetic epistasis by morpholino co-injection in zebrafish followed by in situ hybridization Investigative ophthalmology & visual science Medium 20207966
2012 Silencing IFT80 in murine mesenchymal progenitor cells and bone marrow stromal cells leads to shortening or loss of cilia, decreased Arl13b expression, inhibition of osteoblast marker expression, reduced ALP activity and cell mineralization, and inhibition of Gli2 expression. Overexpression of Gli2 rescued osteoblast differentiation deficiency from IFT80-silenced cells, placing IFT80 upstream of Gli2 in the Hedgehog/Gli signaling pathway during osteogenesis. Lentivirus-mediated RNAi in C3H10T1/2 and bone marrow stromal cells; Gli2 rescue overexpression; Smo agonist (SAG) treatment Bone Medium 22771375
2013 Silencing IFT80 in bone marrow stromal cells impairs cilia formation and chondrogenic differentiation, downregulates Hedgehog signaling, and upregulates Wnt signaling. Overexpression of Gli2 in IFT80-silenced cells promotes chondrogenesis, placing IFT80 upstream of Gli2/Hh signaling and indicating IFT80 inversely regulates Wnt signaling during chondrocyte differentiation. RNAi silencing in mouse bone marrow derived stromal cells; Gli2 rescue overexpression; chondrogenic differentiation assay Experimental cell research Medium 23333501
2019 Conditional deletion of IFT80 in chondrocytes (Col2α1-CreER mice) reduces cilia formation and chondrocyte proliferation in fracture callus, and downregulates TGF-β signaling by inhibiting expression of TGF-βI, TGF-βR, and phosphorylation of Smad2/3, demonstrating IFT80 is required for fracture healing through TGF-β/Smad2/3 signaling in chondrocytes. Conditional knockout mouse model (tamoxifen-inducible Col2α1-CreER); femoral fracture model; microCT; Western blot for p-Smad2/3; primary chondrocyte cultures in vitro Journal of bone and mineral research High 31643106
2019 IFT80 deletion in odontoblast lineage (dental pulp stem cells) reduces DPSC proliferation and differentiation; loss of IFT80 disrupts FGF2-FGFR1-PI3K-AKT signaling and impairs Hedgehog signaling, leading to impaired odontoblast polarization and tooth development. Conditional knockout mouse model; in vitro DPSC culture; signaling pathway analysis Cell death & disease Medium 30683845
2019 In IFT80-deficient dental pulp stem cells, reduced FGFR1 expression disrupts FGF2-FGFR1 signaling, which normally induces stress fiber rearrangement to promote cilia elongation and stimulates PI3K-AKT signaling to activate Hh/BMP2 signaling. Loss of IFT80 decouples these pathways, impairing odontogenic differentiation. IFT80 knockdown in DPSCs; FGFR1 signaling assays; PI3K-AKT pathway analysis; cilia elongation measurement International journal of biological sciences Medium 31592124
2020 Conditional deletion of IFT80 in type II collagen-positive cells causes cilia loss in growth plate and cartilage endplate, disrupts intervertebral disc structure, increases cell apoptosis, and markedly decreases expression of Hedgehog signaling components (Gli1 and Ptch1). Deletion in type I collagen-positive cells disorganizes the outer annulus fibrosus; Smoothened agonist (SAG) rescues OAF cell proliferation and osteogenic differentiation, confirming IFT80 acts upstream of Hh signaling in IVD maintenance. Conditional knockout mouse model (Col2-CreERT and Col1-CreERT); cilia-GFP mice for cilia imaging; SAG rescue experiment; IHC and gene expression analysis FASEB journal Medium 32227389
2022 IFT80 negatively regulates osteoclast differentiation by associating with Cbl-b to promote Cbl-b stabilization and proteasomal degradation of TRAF6. IFT80 knockdown increases ubiquitination of Cbl-b and elevates TRAF6 levels, hyperactivating the RANKL/NF-κB signaling axis and increasing osteoclast formation. Ectopic overexpression of IFT80 rescued osteolysis in a calvarial bone loss model. Myeloid-lineage conditional knockout mice; Co-immunoprecipitation (IFT80-Cbl-b association); ubiquitination assay; RANKL signaling analysis; calvarial osteolysis rescue model Proceedings of the National Academy of Sciences of the United States of America High 35733270
2008 A long isoform of IFT80 (IFT80-L) was identified whose C-terminus shares sequence with IFT80 and whose N-terminus shares sequence with TRIM59; IFT80-L is highly expressed in rapidly proliferating cells but not in differentiated cells that have withdrawn from the cell cycle, as shown by nerve growth factor-induced differentiation assays. Sequence analysis; nerve growth factor-induced cell differentiation assay; expression analysis Biochemical and biophysical research communications Low 18601909
2018 Overexpression of IFT80 in gastric cancer cell lines leads to cilia lengthening, increased proliferation and invasion, increased expression of p75NGFR and MMP9, and treatment with p75NGFR antagonist PD90780 inhibits the invasion increase caused by IFT80 overexpression, placing IFT80 upstream of p75NGFR and MMP9 in a pro-invasive signaling pathway. Stable IFT80 overexpression in gastric cancer cell lines; Matrigel invasion assay; Western blot; pharmacological inhibition with PD90780 International journal of molecular sciences Low 30453504
2022 CRISPR-Cas9-mediated truncation of IFT80 in bovine embryos causes embryonic arrest at the 8-cell stage, when IFT80 is normally activated, and this is associated with disruption of WNT and Hedgehog signaling. CRISPR-Cas9 knockout in bovine embryos (IFT80 transcript truncated at exon 2 or 11); in vitro fertilization; embryo culture Journal of dairy science Medium 36085107
2025 IFT80 deficiency in mesenchymal stem cells downregulates TRPA1 expression and TRPA1-mediated Ca2+ influx, inhibiting AKT and ERK signaling and impairing mechanically-stimulated osteoblastic differentiation. TRPA1 overexpression reverses impaired bone formation in IFT80-deficient mice under exercise training, placing IFT80 upstream of TRPA1-Ca2+-AKT/ERK in mechanical signal transduction. MSC-specific knockout mouse (Prx1Cre; IFT80f/f); mechanical stimulation assay; Ca2+ influx measurement; TRPA1 overexpression rescue in vivo Metabolism: clinical and experimental Medium 39954781
2024 Deletion of IFT80 in Prx1 mesenchymal lineage cells impairs early bone healing of tooth extraction sockets and reduces osteogenic markers in alveolar bone-derived mesenchymal stem cells; TAZ overexpression recovers osteogenic marker expression and migration, and local lentiviral TAZ delivery enhances RUNX2 and OSX expression and promotes socket bone healing, placing IFT80 upstream of the TAZ/RUNX2 pathway. Conditional knockout mouse model (Prx1Cre; IFT80f/f); tooth extraction socket model; TAZ overexpression rescue in vitro and in vivo Oral diseases Medium 38287672

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nature genetics 237 17468754
2011 An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. Human molecular genetics 75 21227999
2009 Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. Journal of medical genetics 56 19648123
2012 The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis. Bone 48 22771375
2013 IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways. Experimental cell research 43 23333501
2010 The intraflagellar transport protein ift80 is essential for photoreceptor survival in a zebrafish model of jeune asphyxiating thoracic dystrophy. Investigative ophthalmology & visual science 39 20207966
2019 IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 31643106
2021 Exosomal circ_IFT80 Enhances Tumorigenesis and Suppresses Radiosensitivity in Colorectal Cancer by Regulating miR-296-5p/MSI1 Axis. Cancer management and research 31 33658855
2020 Ciliary IFT80 is essential for intervertebral disc development and maintenance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 32227389
2019 IFT80 is required for stem cell proliferation, differentiation, and odontoblast polarization during tooth development. Cell death & disease 28 30683845
2019 Ciliary IFT80 regulates dental pulp stem cells differentiation by FGF/FGFR1 and Hh/BMP2 signaling. International journal of biological sciences 22 31592124
2022 IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation. Proceedings of the National Academy of Sciences of the United States of America 16 35733270
2022 Truncation of IFT80 causes early embryonic loss in Holstein cattle associated with Holstein haplotype 2. Journal of dairy science 9 36085107
2018 IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling. International journal of molecular sciences 9 30453504
2008 Identification and characterization of a long isoform of human IFT80, IFT80-L. Biochemical and biophysical research communications 9 18601909
2025 IFT80 and TRPA1 cooperatively regulate bone formation by calcium signaling in response to mechanical stimuli. Metabolism: clinical and experimental 7 39954781
2018 IFT80 mutations cause a novel complex ciliopathy phenotype with retinal degeneration. Clinical genetics 6 29923190
2019 Mutations in IFT80 cause SRPS Type IV. Report of two families and review. American journal of medical genetics. Part A 5 30767363
2025 The IFT80/Hedgehog Pathway Regulates the Osteogenic-adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells. Current medicinal chemistry 4 38644709
2022 The Effect of IFT80 Deficiency in Osteocytes on Orthodontic Loading-Induced and Physiologic Bone Remodeling: In Vivo Study. Life (Basel, Switzerland) 3 36013326
2024 IFT80 promotes early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway. Oral diseases 2 38287672

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