IFT140

IFT140 is a core component of intraflagellar transport complex A (IFT-A) that mediates retrograde protein trafficking within cilia, and its loss perturbs the ciliary localization of anterograde IFT machinery (PMID:22503633). In photoreceptors it is required to move opsin through the connecting cilium; acute Ift140 deletion strands opsin in the inner-segment plasma membrane, a defect distinct from the Golgi-to-cilium-base role of IFT20 (PMID:24619649). The retrograde nature of IFT140 function is evidenced by accumulation of the IFT-B component IFT88 at the ciliary tip when IFT140 is lost or carries pathogenic missense alleles (PMID:30479745), and by mislocalization of IFT-B components IFT27 and IFT88 during spermiogenesis (PMID:29236364). Through primary cilia, IFT140 is required for Hedgehog signaling, with loss producing neural tube, skeletal, and somite patterning defects in mouse embryos and impaired odontoblast differentiation and reparative dentin formation (PMID:24009529, PMID:29195058). Beyond primary cilia, IFT140 is required for motile cilia assembly and beat function, with FOXJ1+ conditional deletion yielding short cilia, reduced beat frequency, and abnormal central-apparatus ultrastructure (PMID:40348912), and is essential for spermiogenesis and sperm flagellum formation, localizing to the neck and mid-piece of human sperm (PMID:29236364, PMID:31397098). IFT140 is delivered from the Golgi to cilia via the ARF-family GTPase ARL16, whose loss traps IFT140 at the Golgi (PMID:35196065). Pathogenic missense mutations reduce IFT140 integration into the IFT-A complex in a domain-specific manner, yet individual mutations cause only mild ciliogenesis defects while IFT140 knockout abolishes cilia, indicating the IFT-A system tolerates partial loss of IFT140 incorporation (PMID:39880085). Mutations in IFT140 cause ciliopathy phenotypes including syndromic and nonsyndromic retinitis pigmentosa, with mutant protein showing reduced basal-body localization (PMID:26968735, PMID:28724397).

1. 2012 Medium

   Established IFT140 as an IFT-A component required for retrograde ciliary transport by linking patient mutations to disrupted ciliary IFT distribution.

   Evidence Immunocytochemistry of IFT components in patient fibroblasts plus Sanger sequencing

   PMID:22503633

   Open questions at the time

   • Did not define which cargoes depend on IFT140
   • No reconstitution of IFT-A complex architecture
2. 2013 Medium

   Connected IFT140 to Hedgehog-dependent developmental patterning, showing its ciliary role is required for a specific signaling output.

   Evidence ENU mutant mouse embryo phenotyping with Hedgehog pathway analysis

   PMID:24009529

   Open questions at the time

   • Molecular step in Hedgehog transduction affected not resolved
   • Single mutant allele
3. 2014 High

   Defined a specific cargo (opsin) and positioned IFT140 in the axonemal transit step, distinct from Golgi-to-base transport mediated by IFT20.

   Evidence Acute conditional Ift140 knockout mouse with immunofluorescence and epistatic comparison to Ift20 knockout

   PMID:24619649

   Open questions at the time

   • Mechanism of opsin recognition by IFT-A not shown
   • Restricted to photoreceptor system
4. 2016 Medium

   Showed that both nonsyndromic retinitis pigmentosa and syndromic IFT140 missense mutations impair basal-body localization, providing a shared cellular mechanism for allelic disease.

   Evidence Transient transfection of hTERT-RPE1 cells with mutant vs wild-type IFT140 and basal-body co-localization imaging

   PMID:26968735

   Open questions at the time

   • Overexpression in transient assay may not reflect endogenous behavior
   • No quantitative link to IFT-A assembly
5. 2017 Medium

   Extended IFT140's Hedgehog role to odontoblast differentiation and dentin repair, and validated a splicing/missense allele as loss-of-function in vivo.

   Evidence Osx-Cre conditional knockout mice with SHH readouts and tooth-drilling model; patient RT-PCR splicing analysis with zebrafish complementation

   PMID:28724397 PMID:29195058

   Open questions at the time

   • Tissue-specific dependence on cilia not generalized
   • Splicing vs missense contribution to phenotype not separated
6. 2018 High

   Demonstrated retrograde defect directly via IFT88 ciliary-tip accumulation and used isogenic rescue to assign causality to a specific missense allele, and established IFT140's role in spermiogenesis.

   Evidence Patient urine renal epithelial cells and CRISPR KO cells with mutant/WT rescue; spermatocyte/spermatid-specific conditional KO mice with EM, IFT localization, and fertility assays

   PMID:29236364 PMID:30479745

   Open questions at the time

   • Why IFT-B components mislocalize without expression change not mechanistically resolved
   • Substrate selectivity of IFT-A in sperm undefined
7. 2019 Medium

   Localized IFT140 to the neck and mid-piece of human sperm and tied biallelic variants to male infertility with structural sperm defects.

   Evidence Immunofluorescence and TEM of patient sperm with exome sequencing and family segregation

   PMID:31397098

   Open questions at the time

   • Single case
   • Causal mechanism of structural defects not dissected
8. 2022 Medium

   Identified ARL16 as a GTPase regulating a selective Golgi-to-cilia export route for IFT140, explaining how IFT140 reaches the cilium.

   Evidence ARL16 knockout MEFs with IFT140 vs other-IFT-protein Golgi localization imaging

   PMID:35196065

   Open questions at the time

   • Direct ARL16-IFT140 interaction not shown
   • Vesicular carrier identity undefined
9. 2025 High

   Quantified, domain-specifically, how missense mutations reduce IFT140 incorporation into IFT-A and revealed functional resilience to partial loss; separately established a dedicated requirement in motile cilia.

   Evidence AP-MS panel of 23 missense mutants with ciliogenesis assays; FOXJ1-Cre conditional KO mice with beat-frequency and ultrastructure analysis

   PMID:39880085 PMID:40348912

   Open questions at the time

   • Structural basis for domain-specific assembly loss not solved
   • How partial complex reduction is buffered not mechanistically defined
10. 2025 Medium

    Uncovered non-ciliary roles in cell polarity and microtubule stabilization rescuable by mTOR/ULK1 inhibition, and a candidate physical partner (Psv) linking IFT-A to Wnt/β-catenin nuclear translocation.

    Evidence Zebrafish ift140 mutants/crispants with polarity and microtubule imaging and pharmacological modifiers; Drosophila Co-IP, NLS mutagenesis, and genetic epistasis (preprint)

    PMID:40924493 PMID:bio_10.1101_2025.06.21.660855

    Open questions at the time

    • Whether non-ciliary phenotypes are independent of cilia loss unresolved
    • Psv-IFT140 interaction is a single Co-IP in Drosophila pending peer review
    • Human relevance of Wnt nuclear translocation role untested

• How IFT140 within IFT-A selects and hands off specific membrane and signaling cargoes, and the structural rules governing mutation-driven complex disassembly, remain unresolved.
• No high-resolution structure of mutant IFT-A assemblies in the corpus
• Cargo-recognition mechanism undefined
• Mechanistic basis of functional resilience to partial IFT140 loss unknown