Affinage

IFT27

Intraflagellar transport protein 27 homolog · UniProt Q9BW83

Length
186 aa
Mass
20.5 kDa
Annotated
2026-04-28
16 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT27 is a Rab-like small GTPase subunit of intraflagellar transport complex B that couples ciliary assembly, BBSome-mediated cargo trafficking, and Hedgehog signaling. IFT27 forms a stable heterodimer with IFT25 and associates with the IFT74–IFT81 dimer within IFT-B; its GTPase activity is required for IFT-B complex association and flagellar entry, and BBS-associated missense variants that disrupt IFT74–IFT81 binding fail to rescue ciliary defects (PMID:19412537, PMID:24843028, PMID:34888642). Inside cilia, IFT27 disengages from IFT-B to interact directly with the nucleotide-free form of ARL6/BBS3, promoting ARL6 activation, BBSome coat assembly, and coordinated retrograde export of signaling receptors including Patched-1 and Smoothened; loss of IFT27 causes ciliary accumulation of BBSome and Hedgehog pathway components and abnormal Gli2 localization (PMID:25443296, PMID:25446516, PMID:38310983). IFT27 is also essential for sperm flagella formation, where its loss disrupts the 9+2 axoneme and destabilizes IFT25 and IFT81, and complete loss-of-function variants in humans cause altered ciliogenesis in fetal kidney, establishing IFT27 as a Bardet-Biedl syndrome gene (PMID:28964737, PMID:34888642, PMID:39955445).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 High

    Identifying IFT27's molecular partnership within IFT-B: IFT25 was shown to directly bind IFT27, forming a heterodimeric subcomplex that co-sediments with IFT complex B, establishing the basic unit through which IFT27 integrates into the IFT machinery.

    Evidence In vitro binding assay and sucrose density gradient centrifugation of Chlamydomonas IFT-B

    PMID:19412537

    Open questions at the time
    • Stoichiometry and affinity of the IFT25–IFT27 dimer not determined
    • How the dimer attaches to the rest of IFT-B was unknown
  2. 2014 High

    Defining the GTPase cycle's role in IFT-B association and flagellar entry: GDP-locked IFT27 failed to associate with IFT-B or enter the flagellum and dominantly blocked flagellum formation, while also being required for IFT-A and IFT dynein import, establishing that IFT27's nucleotide state gates retrograde transport competence.

    Evidence Expression of nucleotide-locked IFT27 mutants in Trypanosoma brucei with co-immunoprecipitation and fluorescence microscopy

    PMID:24843028

    Open questions at the time
    • Identity of the GTPase-activating protein (GAP) and guanine nucleotide exchange factor (GEF) for IFT27 unknown
    • Whether GTPase activity is required in mammalian systems not tested
  3. 2014 High

    Revealing the post-entry function of IFT27 — coupling BBSome export to IFT: two contemporaneous studies showed that IFT27 disengages from IFT-B inside cilia to directly interact with nucleotide-free ARL6/BBS3, promoting its activation and BBSome coat assembly for retrograde export of Patched-1 and Smoothened, with genetic epistasis placing Lztfl1 downstream of IFT27 in BBSome–IFT coupling.

    Evidence Biochemical reconstitution of IFT27–ARL6 binding (proteomics/in vitro assays); Ift27-KO mice with genetic epistasis and immunofluorescence for ciliary cargo

    PMID:25443296 PMID:25446516

    Open questions at the time
    • Structural basis of IFT27–ARL6 interaction not resolved
    • Whether IFT27 acts catalytically as a GEF or as a chaperone for ARL6 is ambiguous
    • How IFT27 disengagement from IFT-B is triggered inside cilia is unknown
  4. 2017 High

    Establishing IFT27's requirement for mammalian sperm flagellogenesis: conditional knockout in spermatocytes caused complete loss of the 9+2 axoneme and disorganization of accessory structures, with concomitant destabilization of IFT25 and IFT81, demonstrating IFT27 stabilizes its IFT-B partners in vivo.

    Evidence Conditional Ift27-KO mice (Stra8-iCre), TEM/SEM, and western blot for IFT subunit levels in testis

    PMID:28964737

    Open questions at the time
    • Whether IFT27 is required for motile cilia in other tissues (e.g. airway) not addressed
    • Mechanism by which IFT27 stabilizes IFT25/IFT81 protein levels unclear
  5. 2021 Medium

    Identifying a reciprocal stabilization circuit: LZTFL1 selectively stabilizes IFT27 protein in male germ cells, revealing bidirectional dependence between the BBSome adaptor pathway and IFT27.

    Evidence Global Lztfl1-KO mice with western blot for IFT subunit levels in testis

    PMID:34023333

    Open questions at the time
    • Mechanism of selective stabilization (direct binding vs. co-degradation) not determined
    • Whether LZTFL1–IFT27 stabilization occurs in non-germline tissues not tested
  6. 2022 High

    Mapping the IFT-B docking site and explaining BBS pathogenesis: BBS-associated IFT27 missense variants were shown to specifically impair binding to IFT74–IFT81 and fail to rescue BBS-like phenotypes, pinpointing the IFT25–IFT27 / IFT74–IFT81 interface as the critical disease-relevant interaction.

    Evidence Co-immunoprecipitation with deletion constructs and IFT27-KO cell rescue with BBS-variant alleles

    PMID:34888642

    Open questions at the time
    • Atomic-resolution structure of the IFT25–IFT27–IFT74–IFT81 interface not available
    • Whether all BBS-associated IFT27 variants act through the same mechanism is untested
  7. 2024 Medium

    Extending IFT27 function to retinal homeostasis and Hedgehog-dependent Gli2 localization: ift27-KO zebrafish showed progressive rod-before-cone photoreceptor degeneration, and IFT27 knockdown in RPE cells impaired Hedgehog signaling and Gli2 ciliary localization.

    Evidence TALEN-generated ift27-KO zebrafish with ERG; siRNA knockdown in human RPE cells with Gli2 immunofluorescence

    PMID:38310983

    Open questions at the time
    • Whether photoreceptor degeneration is a direct consequence of Hedgehog pathway disruption or reflects broader IFT failure
    • Mechanism of Gli2 mislocalization upon IFT27 loss not dissected
  8. 2025 Medium

    Confirming IFT27's requirement for human ciliogenesis: complete loss-of-function IFT27 variants (triggering mRNA decay) caused defective ciliogenesis in human fetal kidney, demonstrating in vivo relevance in humans that was uncertain from mouse somatic studies.

    Evidence Genome sequencing of human fetal cases with mRNA decay confirmation and immunohistochemistry on fetal kidney sections

    PMID:39955445

    Open questions at the time
    • Number of human cases is limited
    • Whether the ciliogenesis defect reflects loss of IFT-B assembly, BBSome coupling, or both is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of IFT27's GAP and GEF, the structural basis of IFT27–ARL6 activation, the mechanism by which IFT27 disengages from IFT-B inside cilia, and whether IFT27 has cilia-independent signaling roles.
  • No GAP or GEF for IFT27 identified
  • No high-resolution structure of the IFT27–ARL6 complex
  • Trigger for intra-ciliary IFT27 release from IFT-B unknown
  • Potential cilia-independent roles (e.g. macrophage MAPK regulation) lack mechanistic depth

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2
Localization
GO:0005929 cilium 4 GO:0005829 cytosol 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 3
Partners
ARL6IFT25IFT74IFT81LZTFL1
Complex memberships
IFT-B complexIFT25–IFT27 heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 IFT27 is a Rab-like GTPase component of IFT complex B that, upon disengagement from the rest of IFT-B inside cilia, directly interacts with the nucleotide-free form of ARL6/BBS3 and prevents its aggregation in solution, thereby promoting ARL6 activation, BBSome coat assembly, and subsequent exit of BBSome and associated signaling receptors from cilia. Unbiased proteomics (mass spectrometry), biochemical reconstitution assays, in vitro binding assays Developmental cell High 25443296
2014 IFT27 links the BBSome to the IFT particle for coordinated removal of patched-1 and Smoothened from cilia during hedgehog signaling; loss of IFT27 causes ciliary accumulation of BBSome, Lztfl1, patched-1, and Smoothened without disrupting ciliary assembly. Genetic epistasis places Lztfl1 downstream of IFT27 in coupling the BBSome to IFT. Ift27 knockout mice, genetic epistasis (double mutant analysis with BBSome and Lztfl1 mutants), immunofluorescence for ciliary protein localization Developmental cell High 25446516
2009 IFT25 is a phosphoprotein component of IFT complex B that directly binds IFT27 in vitro, forming a subcomplex; the two proteins co-sediment at 16S with other complex B subunits in flagella, and their association/dissociation with complex B may regulate IFT. In vitro binding assay, sucrose density gradient centrifugation, dephosphorylation assay, immunofluorescence co-localization (Chlamydomonas ortholog) PloS one High 19412537
2014 IFT27 GTPase activity is required for its association with the IFT-B complex and for entry into the flagellum; a GDP-locked IFT27 cannot enter the flagellum or interact with other IFT-B proteins, and its expression alone prevents flagellum formation. Additionally, IFT27 is required for import of the IFT-A complex and IFT dynein into the flagellar compartment, making it essential for retrograde cargo transport. Expression of GDP- and GTP-locked IFT27 mutants in Trypanosoma brucei (ortholog), co-immunoprecipitation, fluorescence microscopy of flagellar localization eLife High 24843028
2022 The IFT25–IFT27 dimer binds the C-terminal region of the IFT74–IFT81 dimer within the IFT-B complex; BBS-associated missense variants of IFT27 are specifically impaired in IFT74–IFT81 binding and fail to rescue BBS-like phenotypes in IFT27-knockout cells, establishing that impaired IFT25–IFT27 / IFT74–IFT81 interaction underlies BBS-associated ciliary defects. Co-immunoprecipitation, IFT27-knockout cell rescue assays with BBS variants, deletion mapping of IFT74 interaction region Human molecular genetics High 34888642
2017 IFT27 is required for sperm flagella formation and male fertility in mice; conditional knockout in spermatocytes/spermatids causes loss of '9+2' axoneme structure and disorganization of mitochondrial sheath, fibrous sheath, and outer dense fibers. IFT25 and IFT81 protein levels are significantly reduced in IFT27-KO testes, indicating IFT27 stabilizes these IFT-B partners in male germ cells. Conditional knockout mice (Stra8-iCre), histology, TEM, SEM, western blot for IFT protein levels Developmental biology High 28964737
2021 LZTFL1 (BBS17) is an IFT27-associated protein; loss of Lztfl1 in mice significantly decreases testicular IFT27 protein levels without affecting IFT20, IFT81, IFT88, or IFT140, indicating LZTFL1 selectively stabilizes IFT27 in male germ cells. Global Lztfl1 knockout mice, western blot for IFT protein levels in testis Developmental biology Medium 34023333
2021 ATP8a1, a phospholipid flippase involved in translocation of phosphatidylserine and phosphatidylethanolamine across lipid bilayers, is identified as the strongest binding partner of IFT27 in testes; however, knockout of Atp8a1 does not affect male fertility or sperm parameters, suggesting it is dispensable or functionally compensated by ATP8a2. Global Atp8a1 knockout mice, histology, sperm count and motility assays; binding partner identified by pulldown/MS (implied as 'strongest binding partner') Molecular reproduction and development Medium 33821543
2024 In human retinal pigment epithelial cells, decreased IFT27 expression inhibits the Hedgehog signaling pathway and causes abnormal localization of the ciliary mediator Gli2; in ift27 knockout zebrafish, progressive photoreceptor degeneration occurs with late-onset rod-before-cone loss pattern. TALEN-generated ift27 knockout zebrafish, ERG, immunofluorescence for Gli2 ciliary localization in cultured RPE cells with IFT27 knockdown Gene Medium 38310983
2024 In macrophages, IFT27 mediates melatonin's regulation of macrophage polarization; IFT27 knockdown in RAW 264.7 cells increases ERK/JNK phosphorylation, placing IFT27 upstream of MAPK pathway activity in macrophage polarization. DRUG-seq transcriptomics, IFT27 siRNA knockdown in RAW 264.7 cells, western blot for ERK/JNK phosphorylation iScience Low 39100927
2025 Complete loss-of-function IFT27 variants causing mRNA decay are associated with altered ciliogenesis in fetal kidney tissue, demonstrated by immunohistochemistry on kidney sections from human fetal cases, indicating IFT27 is required for ciliogenesis in vivo in humans (in contrast to mouse somatic cells). Functional analysis of human fetal tissue (immunohistochemistry), genome sequencing with mRNA decay confirmation European journal of human genetics Medium 39955445

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Developmental cell 216 25446516
2014 The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Developmental cell 166 25443296
2014 IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. Human molecular genetics 116 24488770
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 68 28964737
2014 The GTPase IFT27 is involved in both anterograde and retrograde intraflagellar transport. eLife 51 24843028
2019 Identification and Characterization of Known Biallelic Mutations in the IFT27 (BBS19) Gene in a Novel Family With Bardet-Biedl Syndrome. Frontiers in genetics 32 30761183
2022 Impaired cooperation between IFT74/BBS22-IFT81 and IFT25-IFT27/BBS19 causes Bardet-Biedl syndrome. Human molecular genetics 31 34888642
2018 Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis. American journal of medical genetics. Part A 14 29704304
2021 Leucine zipper transcription factor-like 1 (LZTFL1), an intraflagellar transporter protein 27 (IFT27) associated protein, is required for normal sperm function and male fertility. Developmental biology 12 34023333
2012 Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, IFT27 and parvalbumin. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 10 23038240
2024 Melatonin alleviates high-fat-diet-induced dry eye by regulating macrophage polarization via IFT27 and lowering ERK/JNK phosphorylation. iScience 7 39100927
2022 Promoter polymorphisms in STK35 and IFT27 genes and their associations with boar sperm freezability. Theriogenology 7 35780559
2025 Complete loss of IFT27 function leads to a phenotypic spectrum of fetal lethal ciliopathy associated with altered ciliogenesis. European journal of human genetics : EJHG 4 39955445
2021 ATP8a1, an IFT27 binding partner, is dispensable for spermatogenesis and male fertility. Molecular reproduction and development 4 33821543
2024 IFT27 regulates the long-term maintenance of photoreceptor outer segments in zebrafish. Gene 0 38310983