Affinage

IFT27

Intraflagellar transport protein 27 homolog · UniProt Q9BW83

Length
186 aa
Mass
20.5 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT27 (RABL4) is a Rab-like small GTPase subunit of intraflagellar transport complex B that links the IFT machinery to BBSome-mediated export of ciliary signaling receptors (PMID:25443296, PMID:25446516). Within IFT-B, IFT27 forms a direct heterodimer with the phosphoprotein IFT25, and this dimer docks onto the C-terminal region of the IFT74-IFT81 dimer; BBS-causing missense variants of IFT27 are selectively impaired in IFT74-IFT81 binding and fail to rescue ciliary export defects (PMID:19412537, PMID:34888642). Upon disengaging from IFT-B inside cilia, IFT27 binds the nucleotide-free form of ARL6/BBS3, preventing its aggregation and promoting GTP loading that drives BBSome coat assembly for ciliary exit, with LZTFL1 acting downstream of IFT27 to couple the BBSome to the IFT particle (PMID:25443296, PMID:25446516). Loss of IFT27 causes accumulation of Patched-1, Smoothened, the BBSome, and LZTFL1 in cilia with defective Hedgehog signaling despite intact ciliary assembly in mouse, and mislocalization of the Hedgehog mediator Gli2 (PMID:25446516, PMID:38310983). IFT27 GTPase competence is required for its own flagellar import and for import of the IFT-A complex and IFT dynein (PMID:24843028). In mammals IFT27 loss produces male infertility from sperm flagellar structural failure with destabilization of a subset of IFT-B components, and progressive photoreceptor degeneration (PMID:28964737, PMID:38310983). IFT27 is mutated in Bardet-Biedl syndrome (BBS19), and complete loss-of-function variants in human fetal cases are associated with altered ciliogenesis (PMID:24488770, PMID:39955445).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Established that IFT27 is a bona fide IFT-B subunit by demonstrating its direct partnership with IFT25 and its incorporation into the larger complex, defining the molecular unit in which IFT27 operates.

    Evidence In vitro binding, sucrose gradient sedimentation and dephosphorylation assays in Chlamydomonas

    PMID:19412537

    Open questions at the time
    • Did not define the GTPase function of IFT27
    • Did not identify the docking site within IFT-B
    • Functional consequence of differential IFT25 phosphorylation unresolved
  2. 2014 High

    Resolved how IFT27 GTPase activity is mechanistically required for IFT, showing nucleotide-locked mutants cannot enter the flagellum or associate with IFT-B and that IFT27 is needed for IFT-A and dynein import.

    Evidence RNAi plus GDP/GTP-locked mutant expression, Co-IP and flagellar import imaging in T. brucei

    PMID:24843028

    Open questions at the time
    • GAP/GEF for IFT27 GTPase cycle not identified
    • Direct mechanism coupling IFT27 to IFT-A/dynein import unresolved
  3. 2014 High

    Defined the signaling output of IFT27 by linking it to BBSome-mediated receptor export, showing IFT27 engages nucleotide-free ARL6/BBS3 to promote GTP loading and BBSome coat assembly, with in vivo accumulation of Patched-1/Smoothened and epistatic placement of LZTFL1 downstream.

    Evidence Proteomics and biochemical reconstitution; Ift27 knockout mice with epistasis to BBSome and Lztfl1 mutants

    PMID:25443296 PMID:25446516

    Open questions at the time
    • Trigger for IFT27 disengagement from IFT-B in cilia unknown
    • Structural basis of IFT27-ARL6 nucleotide exchange not resolved
  4. 2014 Medium

    Connected IFT27 to human disease, identifying it as the causative gene for Bardet-Biedl syndrome (BBS19).

    Evidence Consanguineous family mapping with zebrafish functional validation

    PMID:24488770

    Open questions at the time
    • Single family/single lab identification
    • Mechanism by which variants cause disease not addressed in this study
  5. 2017 High

    Revealed a tissue-specific requirement in spermiogenesis, showing IFT27 is needed for sperm flagellar architecture and for stability of a defined subset of IFT-B components.

    Evidence Conditional Ift27 knockout mice with histology, SEM/TEM, and western blotting for IFT components

    PMID:28964737

    Open questions at the time
    • Why only IFT25 and IFT81 are destabilized is unexplained
    • Whether GTPase activity is required for sperm phenotype not tested
  6. 2021 Medium

    Mapped reciprocal stability dependence within the IFT27 module, showing LZTFL1 is required to maintain IFT27 protein levels in testis.

    Evidence Global Lztfl1 knockout mice, western blotting and immunofluorescence

    PMID:34023333

    Open questions at the time
    • Single method for the IFT27 stability finding
    • Direct physical basis of LZTFL1-mediated stabilization unresolved
  7. 2021 Medium

    Tested the functional relevance of a top IFT27 binding partner, finding ATP8a1 binds IFT27 strongly but is dispensable for spermatogenesis.

    Evidence Pulldown identification of ATP8a1 plus global Atp8a1 knockout sperm analysis

    PMID:33821543

    Open questions at the time
    • Negative functional result; interaction relevance elsewhere untested
    • Single-method interaction evidence
  8. 2022 High

    Pinpointed the structural docking interface and the molecular lesion in disease, showing the IFT25-IFT27 dimer binds the IFT74-IFT81 C-terminus and that BBS variants specifically disrupt this interaction and fail to rescue ciliary export.

    Evidence Reciprocal Co-IP and IFT27-KO cell rescue with BBS variant constructs and ciliary readouts

    PMID:34888642

    Open questions at the time
    • No high-resolution structure of the docked assembly
    • Whether docking regulates IFT27 disengagement timing unknown
  9. 2024 Medium

    Extended the IFT27 loss-of-function phenotype to retinal disease and reaffirmed Hedgehog dependence, linking IFT27 to progressive photoreceptor degeneration and Gli2 mislocalization.

    Evidence ift27 knockout zebrafish with ERG and histopathology; siRNA in RPE cells with Hedgehog readout

    PMID:38310983

    Open questions at the time
    • Cell-autonomous vs systemic basis of photoreceptor loss unresolved
    • Single lab
  10. 2024 Low

    Raised a candidate non-ciliary signaling role, placing IFT27 upstream of MAPK suppression in macrophage polarization.

    Evidence DRUG-seq and IFT27 siRNA in RAW 264.7 macrophages with ERK/JNK phospho-blotting

    PMID:39100927

    Open questions at the time
    • Single knockdown experiment with no mechanistic reconstitution
    • No demonstration of direct IFT27-MAPK link
    • Not validated in primary cells or in vivo
  11. 2025 Medium

    Broadened the human disease spectrum, associating complete loss-of-function IFT27 variants with altered ciliogenesis in fetal tissue, beyond BBSome-mediated signaling.

    Evidence Genome sequencing, mRNA decay analysis and immunohistochemistry on fetal kidney sections

    PMID:39955445

    Open questions at the time
    • Limited to two fetal cases
    • Mechanism linking IFT27 loss to ciliogenesis defect not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The regulatory cycle that controls IFT27 disengagement from IFT-B and its nucleotide state in cilia, and the identity of its GEF/GAP, remain undefined.
  • No identified GEF/GAP for IFT27
  • No structural model of the IFT27-ARL6 exchange step
  • Spatial/temporal trigger of IFT27 release from IFT-B unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9609507 Protein localization 2
Partners
ARL6ATP8A1IFT25IFT74IFT81LZTFL1
Complex memberships
BBSomeIFT complex B

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 IFT25 is a phosphoprotein component of IFT complex B that directly binds IFT27 in vitro, forming a subcomplex; in flagella both proteins co-sediment in 16S fractions with other IFT-B subunits, but 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. In vitro binding assay, sucrose density gradient centrifugation, dephosphorylation assay, immunofluorescence (Chlamydomonas) PloS one High 19412537
2014 IFT27 (RABL4), a Rab-like GTPase component of IFT-B, directly interacts with the nucleotide-free form of ARL6/BBS3 upon disengagement from the rest of IFT-B, prevents aggregation of nucleotide-free ARL6 in solution, and promotes exit of the BBSome and associated cargoes from cilia; GTP loading onto ARL6 drives BBSome coat assembly for ciliary exit. Unbiased proteomics (mass spectrometry), biochemical reconstitution assays, IFT27 knockout/depletion with ciliary accumulation readout Developmental cell High 25443296
2014 Ift27 knockout mice show ciliary accumulation of Patched-1 and Smoothened with defective Hedgehog signaling but intact ciliary assembly; BBSome and Lztfl1 accumulate in Ift27 mutant cilia; because Lztfl1 mutants accumulate BBSome but not IFT27, Lztfl1 functions downstream of IFT27 to couple the BBSome to the IFT particle for coordinated removal of Patched-1 and Smoothened from cilia. Ift27 knockout mice, epistasis analysis with BBSome and Lztfl1 mutants, immunofluorescence for ciliary protein localization, Hedgehog signaling assays Developmental cell High 25446516
2014 In Trypanosoma brucei, IFT27 is essential for anterograde and retrograde intraflagellar transport; loss of IFT27 causes failure to import IFT-A complex and IFT dynein into the flagellar compartment; a GDP-locked (nucleotide-binding deficient) IFT27 cannot enter the flagellum, cannot interact with other IFT-B proteins, and its sole expression prevents flagellum formation, demonstrating that GTPase-competent IFT27 is required for association with the IFT complex. RNAi knockdown in T. brucei, expression of GDP- and GTP-locked IFT27 mutants, co-immunoprecipitation, fluorescence microscopy of flagellar import eLife High 24843028
2014 IFT27 is mutated in Bardet-Biedl syndrome (designated BBS19), establishing it as the first IFT gene implicated in BBS pathogenesis; functional validation in zebrafish confirmed pathogenicity. Human genetics (consanguineous family mapping), zebrafish functional validation Human molecular genetics Medium 24488770
2017 Conditional knockout of Ift27 in mouse spermatocytes/spermatids causes complete male infertility with disrupted sperm flagella (loss of 9+2 axoneme, disorganized mitochondrial sheath, fibrous sheath, and outer dense fibers); IFT25 and IFT81 protein levels are significantly reduced in the testis of conditional Ift27 KO mice, whereas IFT20, IFT74, and IFT140 levels are unchanged, indicating IFT27 is specifically required for stability of a subset of IFT-B components during spermiogenesis. Conditional knockout (Stra8-iCre), histology, SEM, TEM, western blotting for IFT component levels Developmental biology High 28964737
2021 LZTFL1 (BBS17) is an IFT27-associated protein; global Lztfl1 knockout mice show significantly decreased testicular IFT27 protein levels (unlike IFT20, IFT81, IFT88, IFT140 which are stable), indicating LZTFL1 is required for IFT27 stability/maintenance in the testis. Global knockout mice (Lztfl1-KO), western blotting for IFT protein levels, immunofluorescence localization of LZTFL1 during spermiogenesis Developmental biology Medium 34023333
2021 ATP8a1, a phospholipid flippase, is the strongest binding partner of IFT27 (identified by pulldown/binding assay), but global Atp8a1 knockout mice are fertile with normal sperm, demonstrating that this IFT27 binding partner is dispensable for spermatogenesis. Binding/pulldown assay identifying ATP8a1, global Atp8a1 knockout mice, sperm analysis Molecular reproduction and development Medium 33821543
2022 The IFT25-IFT27 dimer binds the C-terminal region of the IFT74-IFT81 dimer within IFT-B; BBS-associated missense variants of IFT27 are specifically impaired in IFT74-IFT81 binding and cannot rescue BBS-like phenotypes in IFT27-KO cells, establishing that the IFT25-IFT27 / IFT74-IFT81 interaction is required for normal BBSome-mediated ciliary membrane protein export. Co-immunoprecipitation, IFT27-KO cell rescue assays with BBS variant IFT27 constructs, ciliary accumulation phenotype readout Human molecular genetics High 34888642
2024 In zebrafish ift27 knockout, IFT27 loss causes progressive photoreceptor degeneration (rods before cones) with impaired ERG; in cultured human retinal pigment epithelial cells, reduced IFT27 expression inhibits the Hedgehog signaling pathway and causes abnormal ciliary localization of the mediator Gli2. TALEN-generated ift27-/- zebrafish, ERG, histopathology, immunofluorescence; siRNA knockdown in RPE cells with Hh pathway readout Gene Medium 38310983
2024 In a melatonin/dry-eye model, IFT27 knockdown in RAW 264.7 macrophages increases ERK/JNK phosphorylation, placing IFT27 upstream of MAPK pathway suppression and suggesting IFT27 mediates melatonin's regulation of macrophage M1 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 in human fetal cases are associated with altered ciliogenesis as shown by immunohistochemistry on fetal kidney sections, expanding the role of IFT27 beyond BBSome-mediated signaling to include ciliogenesis itself in humans. Genome sequencing, mRNA decay analysis, immunohistochemistry on fetal kidney tissue 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 217 25446516
2014 The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Developmental cell 167 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 69 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 13 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 5 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

Missed literature

Know a paper Affinage missed for IFT27? Flag it for the maintainers and the community.

No submissions yet.