IFT140

IFT140 is a core subunit of the intraflagellar transport complex A (IFT-A) that mediates retrograde transport within both primary and motile cilia, functioning in ciliary cargo delivery, signaling, and ciliogenesis across diverse cell types. Loss of IFT140 causes accumulation of IFT-B components (IFT88, IFT27) at the ciliary tip, consistent with defective retrograde transport, and disrupts the ciliary delivery of opsins through the connecting cilium of photoreceptors — acting downstream of IFT20-mediated Golgi-to-base trafficking (PMID:22503633, PMID:24619649, PMID:30479745). IFT140 is required for cilia-dependent Hedgehog signaling in multiple developmental contexts and for motile cilia assembly where its loss produces short cilia with abnormal central apparatus and reduced beat frequency (PMID:24009529, PMID:29195058, PMID:40348912). Trafficking of IFT140 from the Golgi to cilia depends specifically on the ARL16 GTPase, and systematic AP-MS analysis of 23 disease-associated missense mutations reveals domain-specific disruptions of IFT-A complex assembly, although the complex shows resilience to partial IFT140 dysfunction (PMID:35196065, PMID:39880085).

1. 2012 High

   Establishing IFT140 as an IFT-A subunit whose loss alters anterograde IFT component distribution in cilia provided the first direct evidence that IFT140 functions in retrograde intraflagellar transport in human cells.

   Evidence Immunofluorescence of IFT components in patient fibroblasts carrying IFT140 mutations

   PMID:22503633

   Open questions at the time

   • Mechanism by which IFT140 loss alters anterograde IFT component localization not defined
   • Retrograde transport defect inferred from redistribution rather than live cargo tracking
2. 2013 High

   Demonstrating that IFT140 loss-of-function in mice causes Hedgehog signaling defects placed IFT140 within the ciliary Hedgehog transduction pathway, linking retrograde IFT to developmental signaling.

   Evidence ENU mutagenesis mouse model (Cauli allele) with epistasis analysis of Hedgehog pathway outputs

   PMID:24009529

   Open questions at the time

   • Whether IFT140 directly transports Hedgehog pathway effectors (Gli, Smo) or acts indirectly through cilia structure not resolved
   • Hedgehog pathway analysis limited to phenotypic readouts
3. 2014 High

   Conditional Ift140 knockout in photoreceptors showed opsin accumulates at the inner segment plasma membrane rather than the Golgi, distinguishing IFT140's role in moving cargo through the connecting cilium from IFT20's role in Golgi-to-base transport.

   Evidence Conditional/inducible Ift140 KO mouse compared with Ift20 KO; opsin immunofluorescence

   PMID:24619649

   Open questions at the time

   • Direct binding of IFT140 to opsin cargo not demonstrated
   • Whether all photoreceptor cargo depends on IFT140 remains untested
4. 2016 Medium

   Pathogenic IFT140 missense mutations associated with retinitis pigmentosa were shown to reduce IFT140 localization to the basal body, linking disease variants to a specific subcellular trafficking defect.

   Evidence Transfection of mutant vs. wild-type IFT140 constructs in RPE1 cells; basal body immunofluorescence

   PMID:26968735

   Open questions at the time

   • Overexpression system may not recapitulate endogenous protein behavior
   • Impact on retrograde IFT dynamics not measured
5. 2017 Medium

   Conditional deletion of IFT140 in odontoblasts extended the requirement for IFT140 in Hedgehog signaling to dentinogenesis, reinforcing its broad role in cilia-dependent SHH transduction.

   Evidence Ift140flox/Osx-Cre conditional KO mice; SHH pathway marker expression and odontoblast differentiation assay

   PMID:29195058

   Open questions at the time

   • Whether IFT140 requirement reflects general cilia loss or specific cargo transport in odontoblasts not distinguished
6. 2018 High

   IFT140 was shown to be essential for sperm flagella assembly and proper IFT-B component localization during spermiogenesis, extending its function from primary cilia to motile flagella.

   Evidence Conditional Ift140 KO in mouse spermatocytes/spermatids; TEM, immunofluorescence for IFT27/IFT88

   PMID:29236364

   Open questions at the time

   • Whether IFT140 participates in flagellar dynein arm transport not addressed
   • Mechanism of IFT-B mislocalization upon IFT140 loss not defined
7. 2018 Medium

   Demonstration that IFT140 loss causes IFT88 accumulation at the ciliary tip in both patient-derived renal cells and CRISPR KO cells, with a patient missense variant recapitulating the defect, provided direct cellular evidence for impaired retrograde IFT as the primary consequence of IFT140 dysfunction.

   Evidence Patient urine-derived renal epithelial cells and CRISPR Ift140 KO with rescue transfection; immunocytochemistry

   PMID:30479745

   Open questions at the time

   • Cargo identity beyond IFT88 not systematically profiled
   • Rescue only tested with single mutant allele
8. 2019 Medium

   Conditional deletion of IFT140 in pre-osteoblasts demonstrated its requirement for bone formation, broadening the tissue repertoire of IFT140-dependent cilia functions.

   Evidence Ift140 conditional KO mouse (Osx-Cre); micro-CT, histomorphometry, molecular marker analysis

   PMID:31034313

   Open questions at the time

   • Whether the bone phenotype is cilia-dependent or reflects a non-ciliary IFT140 function not tested
9. 2022 Medium

   Identification of ARL16 as specifically required for Golgi-to-cilia trafficking of IFT140, while other IFT proteins were unaffected, revealed a dedicated export pathway for IFT140.

   Evidence Arl16 KO MEFs; immunofluorescence and subcellular fractionation of IFT140 vs. other IFT proteins

   PMID:35196065

   Open questions at the time

   • Whether ARL16 directly binds IFT140 or acts through an adaptor not determined
   • Mechanism of specificity for IFT140 over other IFT-A subunits unknown
10. 2025 High

    Systematic AP-MS of 23 IFT140 missense mutations revealed domain-specific disruptions of IFT-A complex assembly, while functional assays showed the complex is resilient to partial IFT140 dysfunction, providing a genotype–interaction map for disease variants.

    Evidence AP-MS of 23 missense mutants; IFT140 KO ciliogenesis assay in mammalian cells

    PMID:39880085

    Open questions at the time

    • Retrograde transport dynamics not measured for individual mutants
    • Structural basis for domain-specific disruption not resolved
11. 2025 High

    Conditional deletion of IFT140 from FOXJ1+ motile cilia-forming cells demonstrated that IFT140 is specifically required for motile cilia assembly and intraciliary cargo delivery independent of dynein arm docking.

    Evidence FOXJ1-Cre conditional KO; TEM ultrastructure, high-speed video microscopy, immunofluorescence

    PMID:40348912

    Open questions at the time

    • Whether IFT140 transports central apparatus precursors directly not shown
    • Which specific cargo proteins are IFT140-dependent in motile cilia remains undefined
12. 2025 Medium

    Discovery of disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in ift140-deficient zebrafish kidney cells, reversible by mTOR/ULK1 inhibition, suggested a non-ciliary role for IFT140 in kidney epithelial biology.

    Evidence Zebrafish ift140 mutant; immunostaining for polarity and microtubule markers; pharmacological rescue

    PMID:40924493

    Open questions at the time

    • Non-ciliary function not yet separated from indirect consequences of cilia loss
    • Molecular target of IFT140 in microtubule regulation unknown
    • Pharmacological rescue does not establish direct mechanism

• The direct cargo repertoire of IFT140 within the retrograde IFT pathway, the structural basis for its domain-specific interactions with the IFT-A complex, and whether its non-ciliary functions in cell polarity and microtubule regulation are physiologically independent of cilia remain unresolved.
• No systematic identification of direct IFT140-transported ciliary cargoes
• No high-resolution structure of IFT140 within the IFT-A complex
• Non-ciliary vs. ciliary-dependent functions not mechanistically separated