Affinage

IFT25

Intraflagellar transport protein 25 homolog · UniProt Q9Y547

Length
144 aa
Mass
16.3 kDa
Annotated
2026-06-10
9 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT25 is a phosphoprotein subunit of the intraflagellar transport complex B (IFT-B) that governs signal-dependent ciliary trafficking and flagellum assembly rather than core ciliogenesis (PMID:19412537, PMID:22595669). It directly binds the Rab-like GTPase IFT27 to form a mutually stabilizing heterodimer, such that loss of either partner destabilizes the other and reduces broader IFT-B integrity (PMID:19412537, PMID:28430876, PMID:28964737). This IFT25–IFT27 module docks onto the C-terminal region of the IFT74–IFT81 heterodimer within IFT-B; disruption of this interface, including by Bardet-Biedl syndrome variants of IFT27 and IFT74, produces BBS-like ciliary export defects while leaving ciliogenesis intact (PMID:34888642). Functionally, IFT25 is dispensable for somatic ciliary assembly but is specifically required for signal-dependent intraciliary transport of Hedgehog pathway components (Patched-1, Smoothened, Gli2) and for BBSome export from the cilium (PMID:22595669, PMID:28838966). Beyond cilia, IFT25 is essential for sperm flagella formation and male fertility, with germ-cell-restricted abundance and bidirectional intraflagellar mobility that varies across spermatogenic stages, and it contributes to early kidney development through ureteric bud initiation and branching (PMID:28430876, PMID:39561113, PMID:29626631).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2009 High

    Established that IFT25 is a bona fide IFT-B component and identified its direct binding partner, defining the molecular core of its function.

    Evidence In vitro binding, dephosphorylation, sucrose gradient and immunofluorescence in Chlamydomonas IFT mutants

    PMID:19412537

    Open questions at the time
    • Functional consequence of phosphorylation-dependent subcomplex association not resolved
    • Role within intact IFT-B during transport not addressed in vivo
  2. 2012 High

    Separated IFT25's role in ciliary signaling from ciliogenesis, showing it is required for Hedgehog component transport but not cilium assembly.

    Evidence Ift25-null mouse with immunofluorescence of Hedgehog components and pathway activation assays

    PMID:22595669

    Open questions at the time
    • Mechanism by which IFT25 selectively transports Hedgehog cargo unknown
    • Whether transport defect is direct or via IFT-B destabilization not distinguished
  3. 2017 High

    Demonstrated tissue-specific essentiality in male germ cells and mutual stabilization between IFT25 and IFT27, with effects on broader IFT-B integrity.

    Evidence Germ-cell-specific conditional Ift25 and Ift27 knockouts with Western blot, TEM/SEM and fertility assays

    PMID:28430876 PMID:28964737

    Open questions at the time
    • IFT25-specific functions beyond IFT27 (e.g. sperm lipid rafts) not mechanistically defined
    • How flagellar requirement differs from dispensable somatic cilia unexplained
  4. 2017 Medium

    Defined the trafficking step IFT25 controls, showing it is required for BBSome export from rather than entry into the cilium.

    Evidence IFT25 RNAi in Chlamydomonas with BBSome trafficking analysis by immunofluorescence

    PMID:28838966

    Open questions at the time
    • Single-lab RNAi knockdown without rescue
    • Molecular basis of BBSome export coupling to IFT25 unresolved
  5. 2019 Medium

    Confirmed the IFT25–IFT27 interaction occurs within the flagellum during active transport and is needed for proper IFT and flagellum construction across species.

    Evidence Bimolecular fluorescence complementation and RNAi depletion in live Trypanosoma brucei

    PMID:30709917

    Open questions at the time
    • Single-lab study
    • Whether trypanosome IFT requirement maps to the same Hedgehog/BBSome roles in vertebrates unclear
  6. 2022 High

    Pinpointed the IFT25–IFT27 / IFT74–IFT81 docking interface as the structural basis of Bardet-Biedl syndrome ciliary export defects.

    Evidence Knockout cell rescue with separation-of-function BBS variants, co-immunoprecipitation and ciliary phenotype readouts

    PMID:34888642

    Open questions at the time
    • No high-resolution structure of the assembled module reported here
    • How export cargo is selected at this interface not defined
  7. 2025 Medium

    Characterized IFT25 dynamics in sperm flagella, revealing stage-dependent mobility and germ-cell-restricted abundance underlying its fertility role.

    Evidence CRISPR IFT25-GFP knock-in mouse with FRAP, kymography and live imaging of germ cells

    PMID:39561113

    Open questions at the time
    • Single-lab single-study imaging model
    • Functional meaning of immobile fractions in mature sperm unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IFT25-IFT27 selectively recognizes and exports specific cargo (Hedgehog components, BBSome) remains the central open mechanistic question.
  • No structural model of cargo engagement
  • Role of IFT25 phosphorylation in cargo selection untested
  • IFT27-independent functions of IFT25 uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 4 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-162582 Signal Transduction 1
Partners
IFT27IFT74IFT81
Complex memberships
IFT-B

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 IFT25 is a phosphoprotein component of IFT complex B in Chlamydomonas; it directly binds IFT27 (a Rab-like GTPase) in vitro, and the two proteins form a subcomplex. In the cell body, only a fraction of IFT25/IFT27 is integrated into pre-assembled complex B, and cell-body IFT25 found in complex B is preferentially phosphorylated, suggesting phosphorylation-dependent regulation of subcomplex association with IFT-B. Biochemical fractionation of IFT mutants, in vitro binding assay, dephosphorylation assay, sucrose density gradient centrifugation, immunofluorescence PloS one High 19412537
2012 IFT25 is not required for ciliary assembly in mice but is required for signal-dependent transport of Hedgehog pathway components (Patched-1, Smoothened, Gli2) within cilia; Ift25-null mice fail to activate Hedgehog signaling, demonstrating a separable IFT role in signal transduction distinct from ciliogenesis. Ift25 null mouse generation, immunofluorescence for Hedgehog components in cilia, pathway activation assays, phenotypic analysis of mutant mice Developmental cell High 22595669
2017 IFT25 is dispensable for somatic ciliogenesis but essential for sperm flagella formation and male fertility in mice; in Ift25-knockout testes, IFT27 (its direct binding partner) was absent, and IFT20 and IFT81 levels were reduced, indicating IFT25 stabilizes IFT27 and influences broader IFT-B complex integrity in the testis. Conditional male-germ-cell-specific Ift25 knockout mouse, Western blotting, TEM, light microscopy, SEM, fertility assays Biology of reproduction High 28430876
2017 IFT27 (an IFT25-binding partner) is also essential for sperm flagella formation and male fertility in mice; conditional Ift27 knockout causes loss of IFT25 and IFT81 in the testis but not IFT20, IFT74, or IFT140, indicating IFT25 and IFT27 form a mutually stabilizing subcomplex that is specifically required for sperm flagella but not somatic cilia. Unlike Ift25 KO, sperm lipid rafts were normal in Ift27 KO, indicating IFT25 has additional roles beyond IFT27. Conditional Ift27 knockout (Stra8-iCre), Western blotting, TEM, SEM, fertility assays, comparison with Ift25 KO Developmental biology High 28964737
2017 In Chlamydomonas, IFT25 depletion does not impair flagellar assembly or BBSome entry into flagella, but specifically impairs BBSome movement out of (export from) the flagellum; IFT25 depletion causes dramatic reduction of IFT27, consistent with IFT25-IFT27 mutual stabilization. IFT25 RNAi depletion in Chlamydomonas, immunofluorescence, BBSome trafficking analysis Biology open Medium 28838966
2019 In Trypanosoma brucei, IFT25 is a component of the IFT-B complex and interacts with IFT27 within the flagellum during active IFT (shown by bimolecular fluorescence complementation in live cells); IFT25 depletion results in tiny disorganized flagella with accumulation of IFT-B proteins (except IFT27) but not IFT-A proteins, demonstrating that the IFT25–IFT27 module is required for proper IFT and flagellum construction in trypanosomes. Bimolecular fluorescence complementation in live cells, RNAi depletion, immunofluorescence, flagella phenotype analysis Journal of cell science Medium 30709917
2022 The IFT25–IFT27 heterodimer binds the C-terminal region of the IFT74–IFT81 heterodimer within IFT-B; BBS variants of IFT27 are impaired in IFT74–IFT81 binding and cannot rescue BBS-like phenotypes of IFT27-KO cells; BBS variants of IFT74 (which delete the IFT25–IFT27-binding region) rescue ciliogenesis but produce BBS-like ciliary export defects, establishing that impaired IFT25–IFT27 / IFT74–IFT81 interaction underlies BBS-associated ciliary defects. Knockout cell lines, rescue experiments with BBS variant constructs, co-immunoprecipitation, phenotypic readout (ciliogenesis, BBSome export) Human molecular genetics High 34888642
2025 In developing mouse sperm flagella, IFT25-GFP (knock-in) traffics bidirectionally without apparent preference toward or away from the cell body; FRAP and kymograph analyses show mobile and immobile fractions, with trafficking speed depending on spermatogenic stage: unrestricted diffusion early, mobile puncta in developing sperm, and immobile puncta in mature sperm. IFT25-GFP is highly abundant only in testis, consistent with its germ-cell-specific functional requirement. CRISPR/Cas9 IFT25-GFP knock-in mouse, FRAP, kymograph analysis, Western blotting, live imaging of isolated germ cells Biology of reproduction Medium 39561113
2018 Loss of Ift25 in mice causes duplex kidneys (from defects in ureteric bud initiation at earliest metanephric kidney development) and smaller kidneys with reduced branching, but does not cause rapid cyst growth typical of other IFT gene deletions, establishing a role for IFT25 (together with IFT27) in early kidney development distinct from cystogenesis. Ift25 null mouse, histological and morphological analysis of kidney development, comparison with Ift27 mutants Mechanisms of development Medium 29626631

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Developmental cell 183 22595669
2009 Intraflagellar transport (IFT) protein IFT25 is a phosphoprotein component of IFT complex B and physically interacts with IFT27 in Chlamydomonas. PloS one 79 19412537
2017 Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice. Developmental biology 69 28964737
2017 IFT25, an intraflagellar transporter protein dispensable for ciliogenesis in somatic cells, is essential for sperm flagella formation. Biology of reproduction 58 28430876
2022 Impaired cooperation between IFT74/BBS22-IFT81 and IFT25-IFT27/BBS19 causes Bardet-Biedl syndrome. Human molecular genetics 31 34888642
2017 Chlamydomonas IFT25 is dispensable for flagellar assembly but required to export the BBSome from flagella. Biology open 23 28838966
2019 IFT25 is required for the construction of the trypanosome flagellum. Journal of cell science 10 30709917
2018 Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development. Mechanisms of development 10 29626631
2025 Two-directional trafficking of the IFT25 protein in the developing mouse sperm flagella. Biology of reproduction 1 39561113

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