Affinage

IFT70B

Intraflagellar transport protein 70B · UniProt Q8N4P2

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT70B (Fleer/TTC30B/DYF-1) is a tetratricopeptide-repeat (TPR) protein that functions as a peripheral component of the intraflagellar transport-B (IFT-B) complex and is essential for ciliogenesis (PMID:29654116). It associates with the IFT-B core through a direct interaction with the IFT52–IFT88 dimer that requires both its first TPR repeat and a C-terminal α36 helix; loss of either element abolishes binding and the ability to rescue cilia formation, and combined loss of the IFT70A and IFT70B paralogs blocks ciliogenesis even when other IFT-B subunits still assemble at the ciliary base (PMID:29654116). A central role of Fleer/IFT70 is the control of axonemal tubulin post-translational modification: it is required for both tubulin polyglutamylation and polyglycylation in cilia (PMID:17761526, PMID:21262966), acting non-enzymatically to restrict the localization or activity of tubulin glutamyl ligases, with tubulin glutamylation identified as the key downstream effector for ciliogenesis since depletion of the deglutamylase Ccp5 restores glutamylation and rescues multicilia formation in fleer mutants (PMID:24743595). These modifications underlie proper B-tubule ultrastructure, cilia length, and motility (PMID:17761526, PMID:21262966). Beyond axoneme assembly, TTC30B participates in Sonic hedgehog signaling within cilia, showing paralog-specific behavior relative to TTC30A in modulating PKA activity and ciliary Smoothened localization (PMID:38074101).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 Medium

    Established that fleer is an early-acting gene required for pronephric tubule and glomerular function, providing the first in vivo loss-of-function phenotype before any molecular role was known.

    Evidence Forward genetic screen in zebrafish with fluorescent dextran filtration assay and histology

    PMID:9806915

    Open questions at the time
    • Molecular identity and function of the gene product unknown at this stage
    • No link to cilia or IFT established
    • Mechanism connecting gene loss to kidney phenotype undefined
  2. 2007 High

    Identified fleer as a conserved TPR protein (DYF-1 ortholog) required for ciliary tubulin polyglutamylation, linking the gene to axonemal microtubule modification and ultrastructure.

    Evidence Positional cloning, modification-specific immunostaining, EM of cilia, and C. elegans RNAi

    PMID:17761526

    Open questions at the time
    • Whether Fleer acts directly on the modification machinery or indirectly unclear
    • Molecular partners within cilia not defined
    • Mechanism of B-tubule defect not resolved
  3. 2011 High

    Extended Fleer's role to both polyglutamylation and polyglycylation of axonemal tubulin, placing it upstream of or at the level of both modification pathways.

    Evidence Modification-specific antibody staining and double morpholino (ttll3/ttll6) epistasis in zebrafish

    PMID:21262966

    Open questions at the time
    • Does not establish whether Fleer regulates ligases directly
    • Relative contribution of each modification to motility not separated
  4. 2011 Low

    Proposed that Fleer/IFT70 contributes to cargo-specific IFT via interactions with B9d2 and Inversin, extending its role beyond general cilia assembly.

    Evidence Commentary summarizing referenced primary genetic/biochemical interaction studies

    PMID:21731048

    Open questions at the time
    • Reported only in a news-and-views commentary without primary experimental detail in this entry
    • Direct physical interactions not validated here
    • Cargo specificity mechanism undefined
  5. 2013 Medium

    Positioned mouse TTC30B as a bona fide IFT-B subunit by demonstrating direct interactions with IFT52 and other IFT-B proteins and with the kinesin KIF17.

    Evidence IFT-B immunopurification with mass spectrometry, co-IP, and cell-free in vitro co-IP

    PMID:23810713

    Open questions at the time
    • Single lab
    • Functional consequence of KIF17 interaction not tested
    • Stoichiometry and architecture within IFT-B not resolved
  6. 2014 High

    Defined Fleer/Ift70 as a nonenzymatic regulator restricting tubulin glutamyl ligase localization and identified glutamylation as the key downstream effector for ciliogenesis.

    Evidence Zebrafish ccp5 knockdown in fleer mutant background with glutamylated-tubulin immunostaining and ciliogenesis rescue

    PMID:24743595

    Open questions at the time
    • Molecular mechanism by which Fleer restricts TTLLs unknown
    • Direct binding to ligases not shown
  7. 2018 High

    Resolved the structural basis of IFT70 incorporation into IFT-B and showed IFT70A/IFT70B are jointly essential for cilia formation.

    Evidence CRISPR double knockout, rescue, and TPR/α36 deletion mutagenesis with IFT52-IFT88 co-IP in cultured cells

    PMID:29654116

    Open questions at the time
    • Functional divergence between IFT70A and IFT70B not addressed here
    • How IFT70 incorporation relates to tubulin modification role not connected
  8. 2019 Low

    Linked TTC30B to Sonic hedgehog pathway regulation and to synpolydactyly via a missense variant, connecting ciliary IFT function to a human limb phenotype.

    Evidence Whole exome sequencing with linkage, RNAi knockdown in RPE cells, qRT-PCR of Shh targets, and homology modeling

    PMID:31306809

    Open questions at the time
    • RNAi in single cell type with no direct molecular dissection
    • Causality of the variant not functionally proven
    • Mechanism connecting TTC30B to Shh output undefined
  9. 2023 Medium

    Revealed paralog-specific roles in Shh signaling, with TTC30A more strongly modulating PKA-dependent ciliary Smoothened localization than TTC30B, refining how the two paralogs differ functionally.

    Evidence Single/double KO in hTERT-RPE1 cells, rescue with WT/mutant TTC30, Smoothened immunofluorescence, PKA substrate phospho-assays, and MS interactome comparison

    PMID:38074101

    Open questions at the time
    • Single lab
    • TTC30B's specific contribution to Shh remains attenuated and less defined
    • PKA/IFT57 interaction link to synpolydactyly not fully established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how IFT70B's structural role in IFT-B mechanistically couples to its control of tubulin-modifying enzymes and to paralog-specific Shh signaling outputs.
  • Direct molecular mechanism by which IFT70B restricts TTLL ligase localization unknown
  • Functional division of labor between IFT70A and IFT70B not fully mapped
  • No structural model integrating tubulin-modification and Shh-signaling functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005929 cilium 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
IFT52IFT88KIF17TTC30A
Complex memberships
IFT-B

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Zebrafish fleer (flr), encoding a tetratricopeptide repeat (TPR) protein homologous to C. elegans DYF-1, is required for tubulin polyglutamylation in cilia. flr mutant cilia show dramatically reduced polyglutamylated tubulin, shortened cilia, reduced beat amplitude, and ultrastructural defects in microtubule B-tubules. C. elegans dyf-1 was also shown to be required for tubulin polyglutamylation in sensory neuron cilia. Positional cloning, whole-mount immunostaining with anti-polyglutamylated tubulin antibodies, electron microscopy of cilia ultrastructure, C. elegans RNAi knockdown Molecular biology of the cell High 17761526
2011 Zebrafish fleer mutants lack both tubulin polyglutamylation and tubulin glycylation in cilia, indicating that the Fleer/IFT70 TPR protein is required for both types of tubulin post-translational modification. Combined loss of ttll3 (glycylation) and ttll6 (glutamylation) recapitulates the fleer cilia motility and ultrastructural defects, placing Fleer upstream of or at the level of both modification pathways. Antibody staining with modification-specific antibodies (monoglycylated, polyglycylated, glutamylated tubulin) in fleer mutant zebrafish embryos; double morpholino knockdown epistasis The Journal of biological chemistry High 21262966
2014 Fleer/Ift70 acts as a nonenzymatic regulator that restricts subcellular localization or expression of tubulin glutamyl ligases (TTLLs) in cilia. Knockdown of the deglutamylase Ccp5 restores cilia tubulin glutamylation in fleer/ift70 mutants and rescues pronephric multicilia formation, establishing that tubulin glutamylation is the key downstream effector of Fleer/Ift70 in ciliogenesis. Zebrafish morpholino knockdown of ccp5 in fleer mutant background; immunostaining for glutamylated tubulin; epistasis rescue of ciliogenesis defect Molecular biology of the cell High 24743595
2013 Mouse TTC30B (IFT70B ortholog) is a component of the IFT-B complex and directly interacts with multiple IFT-B proteins including IFT52, as well as the kinesin motor KIF17. In vitro co-immunoprecipitation from cell-free expression confirmed direct interactions with several IFT-B subunits. Immunopurification of IFT-B complex from mouse pituitary cells followed by mass spectrometry; co-immunoprecipitation; in vitro cell-free expression followed by co-IP Experimental cell research Medium 23810713
2018 IFT70A and IFT70B together are essential for ciliogenesis; double-knockout cells fail to form cilia even though other IFT-B subunits still assemble at the ciliary base. IFT70 interacts with the IFT52-IFT88 dimer via its 15 consecutive TPR repeats and a short C-terminal helix (α36); deletion of the first TPR or α36 abolishes interaction with IFT52-IFT88 and abrogates rescue of ciliogenesis in IFT70-KO cells. CRISPR/Cas9 double knockout of IFT70A and IFT70B; exogenous expression rescue; deletion mutagenesis of IFT70A TPR repeats and α36; co-immunoprecipitation with IFT52-IFT88 dimer Biology open High 29654116
2011 Fleer (IFT70) and IFT88 interact with axoneme- and basal body-localized factors B9d2 and Inversin to regulate transport of specific ciliary cargo, indicating that Fleer functions in cargo-specific IFT beyond general cilia assembly. Genetic and biochemical interaction studies reported in referenced primary paper (Zhao and Malicki, 2011), summarized in this commentary The EMBO journal Low 21731048
2023 TTC30B (IFT70B) and TTC30A show paralog-specific differences in Sonic hedgehog signaling: TTC30A-specific interaction with PKA catalytic subunit α (PRKACA) modulates ciliary Smoothened localization and Shh pathway activity, whereas TTC30B has an attenuated version of this effect. Mutant TTC30A (but not mutant TTC30B) inhibits ciliary localization of Smoothened independently of Patched1, associated with altered phospho-PKA substrate accumulation. An impaired TTC30A–IFT57 interaction was identified as a potential mechanistic link to synpolydactyly. Single- and double-knockout hTERT-RPE1 cells; rescue with wildtype or mutant TTC30; immunofluorescence of ciliary Smoothened; PKA substrate phosphorylation assays; mass spectrometry interactome comparison of wildtype vs. mutant TTC30A/B Frontiers in molecular biosciences Medium 38074101
2019 A missense variant p.Ala375Val in TTC30B is associated with synpolydactyly (SPD), and RNAi knockdown of TTC30B in human retinal pigment epithelial cells affects activation of the Shh signaling pathway, indicating TTC30B participates in Shh pathway regulation downstream of cilia. Whole exome sequencing and two-point linkage analysis; RNAi knockdown of TTC30B; qRT-PCR of Shh pathway targets; homology modeling of variant Bone Low 31306809
1998 The zebrafish fleer mutation causes distended glomerular capillary loops and cystic tubules in the pronephric kidney, identifying fleer as an early-acting gene required for pronephric tubule function. Forward genetic screen in zebrafish; fluorescent dextran injection to assess glomerular filtration; histological and light microscopy analysis Development (Cambridge, England) Medium 9806915

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function. Development (Cambridge, England) 394 9806915
2007 The zebrafish fleer gene encodes an essential regulator of cilia tubulin polyglutamylation. Molecular biology of the cell 160 17761526
2011 Tubulin tyrosine ligase-like genes ttll3 and ttll6 maintain zebrafish cilia structure and motility. The Journal of biological chemistry 82 21262966
2002 Genetic analysis of photoreceptor cell development in the zebrafish retina. Mechanisms of development 66 11744374
2018 Conditional mutagenesis by oligonucleotide-mediated integration of loxP sites in zebrafish. PLoS genetics 44 30427827
2014 Cytoplasmic carboxypeptidase 5 regulates tubulin glutamylation and zebrafish cilia formation and function. Molecular biology of the cell 42 24743595
2018 Robust interaction of IFT70 with IFT52-IFT88 in the IFT-B complex is required for ciliogenesis. Biology open 40 29654116
2010 Polymers at interfaces and in colloidal dispersions. Advances in colloid and interface science 37 20542257
1981 Binding of porcine pancreatic phospholipase A2 to various micellar substrate analogues. Involvement of histidine-48 and aspartic acid-49 in the binding process. Biochemistry 27 7284311
1984 Interaction of Trimeresurus flavoviridis phospholipase A2 and its fragment with calcium ion. Journal of biochemistry 23 6520120
2008 Adsorption of molecular brushes with polyelectrolyte backbones onto oppositely charged surfaces: a self-consistent field theory. Langmuir : the ACS journal of surfaces and colloids 22 18558731
1989 Nucleotide sequence of the wild-type RAD4 gene of Saccharomyces cerevisiae and characterization of mutant rad4 alleles. Journal of bacteriology 20 2649477
2023 Surface tension measurement and calculation of model biomolecular condensates. Soft matter 13 37791635
2009 Functional genomics of intraflagellar transport-associated proteins in C. elegans. Methods in cell biology 13 20409822
2013 Interaction of mouse TTC30/DYF-1 with multiple intraflagellar transport complex B proteins and KIF17. Experimental cell research 12 23810713
2012 Pressure and density scaling for colloid-polymer systems in the protein limit. Physical review. E, Statistical, nonlinear, and soft matter physics 10 23004756
1991 Attractive and repulsive interactions between and within adsorbed ribonuclease A layers. Proceedings of the National Academy of Sciences of the United States of America 10 1924377
2015 Water uptake profile in a model ion-exchange membrane: conditions for water-rich channels. The Journal of chemical physics 9 25796265
1986 Cyanylation of 3-hydroxybutyrate dehydrogenase. The "essential" sulfhydryl group is not involved in catalysis. Biological chemistry Hoppe-Seyler 9 3013239
2005 Using self-consistent-field theory to understand enhanced steric stabilization by casein-like copolymers at low surface coverage in mixed protein layers. Biomacromolecules 8 16283722
1987 Target size of the ryanodine receptor from junctional terminal cisternae of sarcoplasmic reticulum. Biochemistry 8 3607018
2019 A rare TTC30B variant is identified as a candidate for synpolydactyly in a Chinese pedigree. Bone 7 31306809
2008 Counterion localization in solutions of starlike polyelectrolytes and colloidal polyelectrolyte brushes: a self-consistent field theory. Langmuir : the ACS journal of surfaces and colloids 6 18698859
1997 On the "Anomalous" Adsorption Behavior of Phosvitin. Journal of colloid and interface science 4 9073431
2023 Paralog-specific TTC30 regulation of Sonic hedgehog signaling. Frontiers in molecular biosciences 3 38074101
2011 Understanding cargo specificity in intraflagellar transport. The EMBO journal 3 21731048
2005 Continuum formulation of the Scheutjens-Fleer lattice statistical theory for homopolymer adsorption from solution. The Journal of chemical physics 1 16375563
2026 HOXD12 a candidate gene for a novel form of synpolydactyly. Bone 0 41786235
2024 Polyelectrolyte brush in a cylindrical pore: A Poisson-Boltzmann theory. The Journal of chemical physics 0 39584553

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