Affinage

IFT56

Intraflagellar transport protein 56 · UniProt A0AVF1

Length
554 aa
Mass
64.2 kDa
Annotated
2026-06-10
13 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT56 (TTC26/DYF13/PIFTC3) is a component of intraflagellar transport (IFT) complex B that is selectively required for the transport of motility-related cargo and for the structural integrity of the IFT-B complex within cilia (PMID:24596149, PMID:28264835). It binds directly to the IFT46 subunit of IFT-B, and the resulting IFT46–IFT56 dimer serves as a docking site within the complex (PMID:25340710, PMID:28077622). In mouse mutants, IFT56 is specifically needed for normal ciliary accumulation of core IFT-B proteins (IFT88, IFT81, IFT27) while leaving IFT-A components unaffected, defining its role as an IFT-B-intrinsic scaffold (PMID:28264835). Through this function IFT56 supports ciliogenesis: its loss produces shortened and defective primary cilia and abnormal photoreceptor outer segments (PMID:22718903). IFT56 is required for Hedgehog signal transduction at multiple steps — enabling Gli protein accumulation at the ciliary tip, the dissociation of Gli from Sufu, and the ciliary localization of PRMT7 that methylates GLI2 to permit its nuclear import and activation of Shh-GLI2 targets (PMID:25340710, PMID:28264835, PMID:42178579). These ciliary Hedgehog roles underlie its requirement in ventral spinal cord patterning and intervertebral disc matrix homeostasis (PMID:35210288, PMID:42178579). The IFT46–IFT56 dimer also recruits the homodimeric kinesin-2 motor KIF17 into cilia across the ciliary permeability barrier via KIF17's C-terminal sequence upstream of its nuclear localization signal (PMID:28077622). Beyond the cilium, IFT56 acts as a scaffold that recruits the deubiquitinase MINDY3 to deubiquitinate and stabilize RACK1, activating NFATc1-driven osteoclast differentiation (PMID:42006908).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 Medium

    Established that the DYF-13 orthologue is embedded in an IFT-B macromolecular complex, defining its biochemical context before its specific function was known.

    Evidence Affinity purification, mass spectrometry, and co-IP of PIFTC3 in Trypanosoma brucei

    PMID:20923419

    Open questions at the time
    • Bridging interaction with IFT122 (IFT-A) not validated in other systems
    • No functional consequence of complex membership defined
    • Divergent organism may not reflect mammalian complex composition
  2. 2012 Medium

    Showed that TTC26 is directly required for ciliogenesis, localizing to the transition zone and being needed for cilium formation and length.

    Evidence Immunofluorescence, SEM, siRNA in mIMCD3 cells, and morpholino knockdown in zebrafish

    PMID:22718903

    Open questions at the time
    • Molecular basis of the ciliary defect not resolved
    • Transition zone localization mechanism unknown
    • Morpholino phenotypes not confirmed by genetic mutants
  3. 2014 High

    Distinguished TTC26 from general IFT-B subunits by showing it is selectively required for transport of motility cargo rather than for IFT particle assembly or speed, and that it binds IFT46 directly while controlling the Gli–Sufu dissociation step in Hedgehog signaling.

    Evidence Live imaging, biochemistry and proteomics in Chlamydomonas dyf13 mutants plus zebrafish knockdown; protein interaction assays and Gli/Sufu analysis in hop mouse fibroblasts

    PMID:24596149 PMID:25340710

    Open questions at the time
    • Structural basis of the IFT46–TTC26 interface not resolved
    • How cargo selectivity is achieved mechanistically unclear
    • Mechanism linking IFT56 to Gli–Sufu dissociation not defined
  4. 2017 High

    Defined IFT56 as required for in-cilium IFT-B integrity and as the docking site that imports the kinesin-2 motor KIF17 into cilia.

    Evidence Mouse Ift56 mutant immunofluorescence of IFT-B/IFT-A components and Gli assays; visible immunoprecipitation with KIF17 domain mapping and ciliary entry rescue in mammalian cells

    PMID:28077622 PMID:28264835

    Open questions at the time
    • How the IFT46–IFT56 dimer enables KIF17 barrier crossing mechanistically unknown
    • Whether IFT-B disassembly is cause or consequence of microtubule defects unresolved
    • Other cargos selected by the dimer not catalogued
  5. 2022 Medium

    Confirmed by a clean genetic replication that TTC26 is causally required for ventral spinal cord patterning and locomotor circuit assembly through ciliary Hedgehog signaling.

    Evidence CRISPR knock-in point mutation in Ttc26, histological spinal cord analysis, and fictive locomotion electrophysiology

    PMID:35210288

    Open questions at the time
    • Direct demonstration that floor-plate Hedgehog defects drive the circuit phenotype not shown
    • Cell-type-specific contributions not dissected
  6. 2025 Medium

    Demonstrated that genetic background strongly modifies the severity of IFT56 loss-of-function, mapping a modifier to Chromosome 4.

    Evidence SNP-based mapping in congenic mouse crosses comparing two backgrounds carrying the same Ift56hop allele

    PMID:41352382

    Open questions at the time
    • Modifier gene not identified
    • Molecular mechanism of phenotypic modification unknown
  7. 2026 Medium

    Extended IFT56 function into two new mechanistic arms: ciliary recruitment of PRMT7 to methylate GLI2 for nuclear import, and a non-ciliary scaffold role recruiting MINDY3 to stabilize RACK1 and drive osteoclastogenesis.

    Evidence Flnb/Ttc26 double-heterozygous mice with PRMT7/GLI2 localization and Shh rescue; co-IP, RNA-seq, osteoclast differentiation assays, conditional KO and structural residue mapping

    PMID:42006908 PMID:42178579

    Open questions at the time
    • Direct enzymatic readout of GLI2 methylation by PRMT7 in cilia not shown
    • Structural model of the MINDY3/RACK1 scaffold residues not experimentally solved
    • Relationship between ciliary and non-ciliary scaffold functions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the IFT46–IFT56 dimer achieves cargo selectivity and what governs the choice between ciliary IFT-B and non-ciliary scaffold functions remains unresolved.
  • No high-resolution structure of the IFT46–IFT56 dimer with cargo
  • Full repertoire of motility cargo dependent on IFT56 not defined
  • Regulatory switch between cilium-resident and cytoplasmic roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 4
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
IFT46KIF17MINDY3PRMT7RACK1
Complex memberships
IFT complex B

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TTC26/DYF13 is a component of IFT complex B in both mammalian cells and Chlamydomonas reinhardtii, as demonstrated by biochemical fractionation and live imaging. In dyf13 mutant flagella, IFT particle assembly and speed are normal (unlike other IFT complex B mutants), but a specific subset of motility-related proteins is depleted, indicating TTC26 is selectively required for transport of motility cargo rather than general IFT. Live imaging, biochemical fractionation, proteomic analysis of dyf13 mutant flagella in Chlamydomonas; morpholino knockdown in zebrafish eLife High 24596149
2014 Wild-type Ttc26 binds directly to the Ift46 subunit of IFT complex B, as shown by protein-protein interaction assays. Loss of Ttc26 impairs Hedgehog signaling by blocking Gli dissociation from Sufu after Gli accumulates at the ciliary tip, rather than preventing Gli accumulation itself. Protein-protein interaction assay (co-IP/pulldown), analysis of Gli localization and Sufu interaction in embryonic fibroblasts from hop (Ttc26 mutant) mice PLoS genetics High 25340710
2017 KIF17 (a homodimeric kinesin-2) interacts with the IFT46-IFT56 dimer within the IFT-B complex through its C-terminal sequence immediately upstream of its nuclear localization signal (NLS), as shown by visible immunoprecipitation assay. This interaction is required for KIF17 entry into cilia across the ciliary permeability barrier, but not for intraciliary trafficking once inside. Visible immunoprecipitation (VIP) assay, domain mapping with C-terminal truncations/mutations, ciliary entry rescue experiments in mammalian cells Molecular biology of the cell High 28077622
2017 IFT56 is specifically required for the integrity of the IFT-B complex within cilia: in Ift56 mouse mutants, core IFT-B proteins (IFT88, IFT81, IFT27) fail to accumulate normally inside cilia, leading to abnormal ciliary microtubule doublet positioning/number and failure to accumulate Gli proteins, causing defective Shh signaling. IFT-A components and IFT-A-dependent proteins are unaffected. Mouse genetic mutant analysis, immunofluorescence of IFT-B/IFT-A components in cilia, Gli accumulation assays, limb and neural tube patterning readouts Development (Cambridge, England) High 28264835
2012 Ttc26 localizes to the transition zone of photoreceptor sensory cilia and primary cilia in mIMCD3 renal cells. Knockdown of Ttc26 in mIMCD3 cells produces shortened and defective primary cilia, and morpholino knockdown in zebrafish causes ciliary defects in the pronephric kidney and shortened/absent photoreceptor outer segments, establishing a direct requirement for Ttc26 in ciliogenesis. Immunofluorescence localization, scanning electron microscopy, morpholino knockdown in zebrafish, siRNA knockdown in mIMCD3 cells Molecular biology of the cell Medium 22718903
2010 In Trypanosoma brucei, the DYF-13 orthologue PIFTC3 participates in a ~660 kDa macromolecular complex containing multiple IFT complex B components and putative IFT factors (DYF-1, DYF-3, DYF-11/Elipsa, IFTA-2), as identified by affinity purification and mass spectrometry. Co-immunoprecipitation also detected an interaction between PIFTC3 and IFT122 (IFT complex A), suggesting a bridging role between IFT-A and IFT-B. Affinity purification and mass spectrometry, co-immunoprecipitation in T. brucei Molecular microbiology Medium 20923419
2022 A CRISPR-replicated point mutation in Ttc26 recapitulates the hop mouse morphological phenotype (absent ventral midline, fused lumbar spinal cord, misplaced notochord, reduced ventral progenitor domains), directly demonstrating that TTC26 is required for normal ventral spinal cord patterning and CPG circuit assembly, likely through ciliary Hedgehog signaling in the floor plate. CRISPR knock-in of point mutation in Ttc26, histological analysis of spinal cord morphology, fictive locomotion electrophysiology eNeuro Medium 35210288
2026 TTC26 acts as a scaffold protein that recruits the deubiquitinase MINDY3 to promote K48-linked deubiquitination of RACK1, thereby stabilizing RACK1 protein and activating NFATc1 transcription factor to drive osteoclast differentiation. Six specific TTC26 residues (N533, T534, E537, R541, K545, K548) are essential for this scaffold activity, identified by structural analysis. Co-immunoprecipitation, Western blotting, RNA sequencing, in vitro osteoclast differentiation assays, protein structural analysis, osteoclast-specific Ttc26 conditional knockout and shRNA knockdown in OVX mice Journal of orthopaedic translation Medium 42006908
2026 TTC26 is required for the localization of protein arginine methyltransferase 7 (PRMT7) to the primary cilium, enabling methylation of the transcription factor GLI2. This ciliary methylation of GLI2 is required for its subsequent nuclear import (mediated by FLNB binding to methylated GLI2), thereby activating Shh-GLI2 signaling and maintaining intervertebral disc matrix homeostasis. Mouse double heterozygous (Flnb/Ttc26) genetic model, transcriptomic analysis, cellular localization of PRMT7 and GLI2, Shh signaling rescue in vivo Genome biology Medium 42178579
2025 A modifier locus for the Ift56hop phenotype maps to Chromosome 4 in mice, as shown by SNP-based mapping comparing Balb/cByJ (viable, hopping adult) and C57BL/6J (perinatal lethal with multiple organ defects including tracheoesophageal fistulas) backgrounds carrying the same Ift56hop mutation. This demonstrates that genetic background dramatically modifies IFT56 loss-of-function phenotypic severity. SNP mapping in congenic mouse crosses, phenotypic characterization of Ift56hop across two genetic backgrounds Developmental biology Medium 41352382

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella. eLife 62 24596149
2017 Ciliary entry of KIF17 is dependent on its binding to the IFT-B complex via IFT46-IFT56 as well as on its nuclear localization signal. Molecular biology of the cell 51 28077622
2017 IFT56 regulates vertebrate developmental patterning by maintaining IFTB complex integrity and ciliary microtubule architecture. Development (Cambridge, England) 33 28264835
2012 Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish. Molecular biology of the cell 25 22718903
2014 A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling. PLoS genetics 24 25340710
2010 Biochemical analysis of PIFTC3, the Trypanosoma brucei orthologue of nematode DYF-13, reveals interactions with established and putative intraflagellar transport components. Molecular microbiology 19 20923419
2020 Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy. Clinical genetics 12 32617964
2021 Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations. Molecular syndromology 10 34177428
2023 A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype. American journal of medical genetics. Part A 3 38135897
2022 Hop Mice Display Synchronous Hindlimb Locomotion and a Ventrally Fused Lumbar Spinal Cord Caused by a Point Mutation in Ttc26. eNeuro 3 35210288
2026 TTC26 scaffolds MINDY3-mediated RACK1 deubiquitination to drive osteoclastogenesis and pathological bone resorption. Journal of orthopaedic translation 0 42006908
2026 FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis. Genome biology 0 42178579
2025 Genetic background influences the extent and severity of cilia-related congenital anomalies in Ift56/Ttc26 mutant mice. Developmental biology 0 41352382

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