Affinage

IFT80

Intraflagellar transport protein 80 homolog · UniProt Q9P2H3

Length
777 aa
Mass
88.0 kDa
Annotated
2026-04-28
21 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT80 is a component of intraflagellar transport complex B that is essential for ciliogenesis and cilium-dependent signaling across multiple tissues. IFT80 is required for Hedgehog pathway activation upstream of Gli2/Gli1, and loss of IFT80 impairs osteoblast, chondrocyte, and odontoblast differentiation through disruption of Hh, TGF-β/Smad2/3, FGF/AKT, and TAZ/RUNX2 signaling, with Gli2 overexpression rescuing differentiation defects in multiple mesenchymal cell types (PMID:22771375, PMID:23333501, PMID:31643106, PMID:38287672). In osteoclasts, IFT80 functions independently of cilia by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6, thereby suppressing RANKL/NF-κB–driven osteoclastogenesis (PMID:35733270). IFT80 also couples cilia-based mechanosensing to bone formation through regulation of TRPA1 expression and Ca²⁺/AKT/ERK signaling (PMID:39954781).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2007 High

    Establishing IFT80 as an essential ciliogenesis factor resolved the question of whether this WD-repeat protein functions within the intraflagellar transport machinery, as knockdown in two divergent organisms produced cilia loss and associated tissue phenotypes.

    Evidence Morpholino knockdown in zebrafish (cystic kidneys) and Tetrahymena (shortened/absent cilia)

    PMID:17468754

    Open questions at the time
    • Precise position within IFT-B subcomplex not defined
    • Mechanism of IFT80 contribution to IFT particle assembly unknown
  2. 2010 High

    Demonstrating that IFT80 loss disrupts photoreceptor outer segment formation and causes opsin mislocalization extended its role from general ciliogenesis to specialized ciliary cargo transport, while altered IFT protein stability suggested a particle-maintenance function.

    Evidence Morpholino knockdown in zebrafish; TEM, immunohistochemistry, and Western blot

    PMID:20207966

    Open questions at the time
    • Whether IFT80 directly stabilizes other IFT-B subunits or acts indirectly is unresolved
    • Cargo specificity for outer segment transport not identified
  3. 2011 High

    Showing that hypomorphic IFT80 cells retain cilia but lose Hedgehog responsiveness separated IFT80's signaling role from its structural ciliogenesis function, establishing a dual requirement.

    Evidence Gene-trap hypomorphic mouse model; Hedgehog agonist stimulation of MEFs

    PMID:21227999

    Open questions at the time
    • Molecular mechanism by which IFT80 enables Hh signal transduction within cilia not determined
    • Whether IFT80 directly affects Smoothened trafficking is unknown
  4. 2012 Medium

    Epistasis experiments placing IFT80 upstream of Gli2 in osteoblast and chondrocyte differentiation defined the signaling hierarchy through which IFT80 controls mesenchymal cell fate via Hedgehog signaling.

    Evidence RNAi knockdown in mesenchymal progenitors; Gli2 overexpression rescue of osteoblast and chondrocyte differentiation

    PMID:22771375 PMID:23333501

    Open questions at the time
    • Whether IFT80 acts on Gli2 transcription, processing, or trafficking is undefined
    • Wnt pathway upregulation upon IFT80 loss lacks mechanistic explanation
    • Single-lab findings
  5. 2019 Medium

    Conditional knockout studies in chondrocytes and dental cells broadened IFT80's signaling repertoire beyond Hedgehog to TGF-β/Smad2/3 and FGF2/FGFR1/PI3K-AKT, showing tissue-specific pathway coupling through cilia.

    Evidence Col2α1-CreER and odontoblast-lineage conditional KO mice; Western blot for Smad2/3 phosphorylation; FGFR1 rescue in DPSCs

    PMID:30683845 PMID:31592124 PMID:31643106

    Open questions at the time
    • Whether IFT80 directly regulates FGFR1 expression or acts indirectly through cilia structure is unclear
    • Whether TGF-β pathway effects are cilia-dependent was not directly tested
  6. 2022 High

    Identifying a cilia-independent, cytoplasmic function of IFT80 — physical association with Cbl-b to promote TRAF6 proteasomal degradation — resolved how IFT80 suppresses osteoclastogenesis through the RANKL/NF-κB axis.

    Evidence Myeloid-specific conditional KO mice; co-immunoprecipitation of IFT80–Cbl-b; ubiquitination assays; in vivo calvarial rescue

    PMID:35733270

    Open questions at the time
    • Whether IFT80 is a direct Cbl-b substrate adaptor or enhances Cbl-b E3 activity is not resolved
    • Structural basis of IFT80–Cbl-b interaction unknown
    • Whether this cilia-independent role extends to other cell types is untested
  7. 2024 Medium

    Placing IFT80 upstream of the TAZ/RUNX2 axis in alveolar bone MSCs added another downstream effector branch and demonstrated IFT80's importance in bone regeneration contexts.

    Evidence Prx1Cre conditional KO mice; tooth extraction socket model; TAZ overexpression rescue

    PMID:38287672

    Open questions at the time
    • Whether TAZ is activated through cilia-dependent mechanotransduction or Hh signaling is not distinguished
    • Single-lab finding
  8. 2025 Medium

    Demonstrating that IFT80 regulates TRPA1 expression and Ca²⁺ influx to drive mechanostimulation-induced osteogenesis via AKT/ERK linked IFT80's ciliary mechanosensing function to a specific ion channel effector.

    Evidence Prx1Cre conditional KO mice; exercise model; Ca²⁺ influx measurement; TRPA1 overexpression rescue

    PMID:39954781

    Open questions at the time
    • Whether IFT80 directly regulates TRPA1 transcription or localization is unknown
    • How TRPA1-mediated Ca²⁺ feeds into AKT/ERK in this context is not mechanistically resolved
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which IFT80 enables Hedgehog signal transduction within cilia — whether through Smoothened or Gli trafficking, processing, or other means — remains undefined, and how IFT80's cilia-dependent and cilia-independent functions are coordinated across cell types is unresolved.
  • No structural model of IFT80 within the IFT-B complex
  • Mechanism of Smoothened/Gli trafficking by IFT80 not established
  • How cilia-dependent and cilia-independent (Cbl-b/TRAF6) functions are differentially regulated is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 4 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 5 R-HSA-392499 Metabolism of proteins 1
Partners
CBL-BGLI2TRAF6TRPA1
Complex memberships
IFT complex B

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 IFT80 is a component of the intraflagellar transport (IFT) machinery required for cilia formation; morpholino knockdown of ift80 in zebrafish caused cystic kidneys, and knockdown in Tetrahymena produced shortened or absent cilia, establishing IFT80 as essential for ciliogenesis in vivo. Morpholino knockdown in zebrafish and Tetrahymena; loss-of-function phenotypic analysis Nature genetics High 17468754
2010 Loss of ift80 in zebrafish disrupts photoreceptor outer segment formation, causes opsin mislocalization in rods and cones, and shortens kinocilia of the ear and motile cilia in the kidney; Western blot analysis revealed a slight increase in the stability of other IFT proteins upon ift80 loss, suggesting Ift80 functions as a maintenance factor for the IFT particle. Morpholino knockdown, transmission electron microscopy, immunohistochemistry, Western blot Investigative ophthalmology & visual science High 20207966
2011 Hypomorphic Ift80 mouse embryonic fibroblasts show significant reduction in Hedgehog pathway activation in response to Hedgehog agonist treatment without loss or malformation of cilia, demonstrating that IFT80 has an absolute requirement in Hh signaling that is separable from its role in ciliogenesis. Gene-trap hypomorphic mouse model; Hedgehog pathway activation assay in mouse embryonic fibroblasts; phenotypic analysis Human molecular genetics High 21227999
2012 Silencing IFT80 in murine mesenchymal progenitor cells causes shortening or loss of cilia, decreases Arl13b expression, inhibits osteoblast marker expression and ALP activity, and downregulates Gli2; Gli2 overexpression rescues the osteoblast differentiation defect, placing IFT80 upstream of Gli2 in the Hedgehog/Gli signaling pathway during osteogenesis. Lentivirus-mediated RNAi in C3H10T1/2 and bone marrow stromal cells; ALP assay; mineralization assay; rescue by Gli2 overexpression Bone Medium 22771375
2013 Silencing IFT80 in mouse bone marrow stromal cells impairs cilia formation, downregulates Hh signaling (Gli2), and upregulates Wnt signaling, inhibiting chondrogenic differentiation; Gli2 overexpression in IFT80-silenced cells promotes chondrogenesis, placing IFT80 as a regulator of both Hh and Wnt pathways in chondrocyte differentiation. RNAi knockdown; chondrogenic differentiation assay; pathway activation assays; rescue by Gli2 overexpression Experimental cell research Medium 23333501
2019 Conditional deletion of IFT80 in chondrocytes (Col2α1-CreER mice) reduces cilia formation, chondrocyte proliferation, and downregulates TGF-β signaling (TGF-βI, TGF-βR, and phospho-Smad2/3) in fracture callus, establishing IFT80 as required for fracture healing through the TGF-β/Smad2/3 pathway in chondrocytes. Conditional knockout mice; microCT; immunohistochemistry; in vitro primary chondrocyte culture; Western blot for Smad2/3 phosphorylation Journal of bone and mineral research High 31643106
2019 Deletion of IFT80 in odontoblast lineage disrupts dental pulp stem cell (DPSC) proliferation via impaired FGF2-FGFR1-PI3K-AKT signaling, and disrupts odontoblast differentiation via Hedgehog signaling; IFT80-deficient DPSCs show reduced FGFR1 expression, establishing IFT80 as an upstream regulator of both FGF/AKT and Hh pathways in tooth development. Conditional knockout mice; DPSC culture; Western blot; pathway inhibition/rescue assays 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 for odontogenic differentiation; loss of IFT80 uncouples these cooperative signaling mechanisms. IFT80 knockdown/KO in DPSCs; FGFR1 rescue; Western blot; actin cytoskeleton imaging; cilia length 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, disorganizes intervertebral disc structure, increases cell apoptosis, and decreases expression of Hh signaling components Gli1 and Patched1; deletion in type I collagen-positive cells disorganizes outer annulus fibrosus, and Smoothened agonist rescues OAF cell proliferation, placing IFT80 upstream of Hh signaling in intervertebral disc maintenance. Conditional knockout mice (Col2-creERT and Col1-creERT); histology; immunohistochemistry; Smo agonist (SAG) rescue FASEB journal Medium 32227389
2022 IFT80 (an IFT complex B protein) negatively regulates osteoclast differentiation by physically associating with the E3 ubiquitin ligase Cbl-b to promote proteasomal degradation of TRAF6; IFT80 knockdown increases Cbl-b ubiquitination and elevates TRAF6 levels, thereby hyperactivating RANKL/NF-κB signaling and enhancing osteoclast formation; IFT80 overexpression rescues osteolysis in a calvarial model. Myeloid-specific conditional KO mice; co-immunoprecipitation (IFT80-Cbl-b association); ubiquitination assay; TRAF6 protein level analysis; calvarial rescue model by IFT80 overexpression Proceedings of the National Academy of Sciences of the United States of America High 35733270
2025 IFT80 deficiency in mesenchymal stem cells (Prx1Cre; IFT80f/f mice) downregulates transient receptor potential ankyrin 1 (TRPA1) expression and TRPA1-mediated Ca2+ influx, which inhibits mechanical stimulation-induced osteoblastic differentiation via AKT and ERK signaling pathways; TRPA1 overexpression reverses the impaired bone formation. MSC-specific conditional KO mice; exercise/mechanical stimulation; Ca2+ influx measurement; TRPA1 overexpression rescue; Western blot for AKT and ERK Metabolism: clinical and experimental Medium 39954781
2024 Deletion of IFT80 in Prx1 mesenchymal lineage cells reduces osteogenic markers and impairs migration/proliferation of alveolar bone-derived MSCs; TAZ overexpression rescues these defects and upregulates RUNX2 and OSX, placing IFT80 upstream of the TAZ/RUNX2 pathway in osteogenesis. Prx1Cre conditional KO mice; tooth extraction socket model; lentivirus-mediated TAZ overexpression rescue; immunofluorescence; ALP/TRAP staining Oral diseases Medium 38287672
2008 A long isoform of human IFT80 (IFT80-L) was identified; sequence analysis indicates it is an evolutionarily merged product of IFT80 and TRIM59 genes, sharing the C-terminal protein sequence with IFT80; IFT80-L is ubiquitously expressed and is highly expressed in rapidly proliferating cells but not in NGF-differentiated (cell cycle-withdrawn) cells. Sequence analysis; expression analysis by RT-PCR; NGF-induced differentiation assay Biochemical and biophysical research communications Low 18601909

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 38 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 27 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 13 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
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
2025 IFT80 and TRPA1 cooperatively regulate bone formation by calcium signaling in response to mechanical stimuli. Metabolism: clinical and experimental 4 39954781
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