Affinage

IFT43

Intraflagellar transport protein 43 homolog · UniProt Q96FT9

Length
208 aa
Mass
23.5 kDa
Annotated
2026-06-10
36 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT43 is a small subunit of the intraflagellar transport complex A (IFT-A) that is essential for retrograde ciliary transport from the ciliary tip back to the base (PMID:21378380). Within IFT-A it directly binds IFT121 and, together with IFT139, forms a 'peripheral' or 'satellite' subcomplex that associates with the IFT122/IFT140/IFT144 core via an IFT121–IFT122 interaction; a fraction of cellular IFT43 also exists independently of the assembled complex (PMID:22170070, PMID:27932497). Consistent with its role in the transport machinery, IFT43 moves as retrograde IFT particles within cilia at the same velocity as the anterograde machinery (PMID:25243405), and its loss causes abnormal accumulation of IFT-B proteins at the ciliary tip while anterograde transport persists (PMID:21378380). Disruption of IFT43 reduces cilia number and length and impairs ciliogenesis (PMID:28973684, PMID:41648367), and it regulates the ciliary trafficking of GPCR cargo: IFT43 physically binds the EP4 receptor through its third intracellular loop and C-terminus and cooperates with the GTPase Rab23 to deliver EP4 to cilia (PMID:41372612). IFT43 is required for Hedgehog signal transduction, where its loss blocks Gli1 induction, causes Gli2/Gli3 to accumulate at ciliary tips, and prevents proper resolution of Gli activator and repressor forms (PMID:41648367). Mutations in IFT43 cause human ciliopathies including Sensenbrenner syndrome (PMID:21378380), short-rib polydactyly syndrome with growth-plate abnormalities (PMID:28400947), and recessive retinal degeneration (PMID:28973684).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Established that IFT43 is a component of the IFT-A machinery specifically required for retrograde, not anterograde, ciliary transport, defining its core cellular function.

    Evidence Western blot of a translation-disrupting mutation and ciliary immunofluorescence of IFT proteins in Sensenbrenner syndrome patient fibroblasts

    PMID:21378380

    Open questions at the time
    • Did not resolve IFT43's position or binding partners within IFT-A
    • Mechanism of retrograde turnaround not addressed
  2. 2011 High

    Defined IFT43's molecular placement by showing it directly binds IFT121 and exists partly as a free pool, indicating a distinct peripheral arm of IFT-A.

    Evidence Yeast two-hybrid, recombinant pulldown, sucrose gradients and mutant analysis in Chlamydomonas

    PMID:22170070

    Open questions at the time
    • Function of the free ~2S IFT43 pool unknown
    • How the peripheral arm engages the core not resolved in this study
  3. 2016 High

    Resolved IFT-A architecture, placing IFT43 in a peripheral subcomplex (IFT43/IFT121/IFT139) that attaches to the core via IFT121-IFT122, and linked peripheral disruption to GPCR mistrafficking.

    Evidence Visible immunoprecipitation interaction mapping and CRISPR knockout of IFT139 vs IFT144 in hTERT-RPE1 cells with ciliary GPCR imaging

    PMID:27932497

    Open questions at the time
    • IFT43 itself was inferred from IFT139-KO phenocopy rather than directly knocked out here
    • Mechanism coupling peripheral arm to retrograde motor unresolved
  4. 2013 Medium

    Identified an upstream regulator, showing the small GTPase Rsg1 controls cytoplasmic localization of IFT43 in multiciliated cells.

    Evidence Morpholino knockdown and live IFT imaging in Xenopus multiciliated cells

    PMID:24192041

    Open questions at the time
    • Direct Rsg1-IFT43 interaction not demonstrated
    • Single model organism and single lab
  5. 2014 Medium

    Demonstrated IFT43 is physically conveyed as retrograde IFT cargo by measuring its transport velocity in cilia.

    Evidence Live fluorescence imaging of OFP::IFT43 in mouse IMCD-3 cells with velocity quantification

    PMID:25243405

    Open questions at the time
    • Does not establish what drives IFT43 turnaround at the tip
    • Single lab
  6. 2017 Medium

    Used IFT43 tip accumulation as a readout to show the IFT-B protein IFT54 mediates tip turnaround, contextualizing IFT43 within the retrograde handoff.

    Evidence Genetic complementation in Chlamydomonas ift54 mutants with IFT43 immunofluorescence/immunoblot

    PMID:28417161

    Open questions at the time
    • IFT43 is the readout, not the manipulated subject
    • Direct IFT43-IFT54 relationship not tested
  7. 2017 Medium

    Linked IFT43 dysfunction to specific human ciliopathies, connecting its ciliogenesis role to skeletal and retinal disease.

    Evidence Exome sequencing, growth-plate histology and ciliogenesis assays in SRPS patient cells; mutant IFT43 expression and cilium-length assays in mIMCD3/MDCK cells for retinal degeneration

    PMID:28400947 PMID:28973684

    Open questions at the time
    • Molecular basis of the cilia-shortening phenotype not defined
    • Tissue-specific requirements not dissected
  8. 2025 Medium

    Defined a direct cargo-handling role, showing IFT43 binds the EP4 GPCR and cooperates with Rab23 to traffic it into cilia.

    Evidence siRNA screen, reciprocal co-IP and domain mapping with EP4, and ciliary EP4 imaging in zebrafish and mammalian cells

    PMID:41372612

    Open questions at the time
    • Whether IFT43-EP4 binding is direct or complex-mediated not fully resolved
    • Mechanism of Rab23 cooperation unknown
  9. 2026 Medium

    Established the in vivo requirement of IFT43 for development and Hedgehog signaling via control of ciliary Gli2/Gli3 dynamics and activator/repressor balance.

    Evidence Mouse Ift43 knockout with Gli2/Gli3/Smoothened ciliary imaging, SAG-induced Gli1 induction, and Gli2 cleavage assays (preprint)

    PMID:41648367

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Direct IFT43-Gli interaction not shown
    • How retrograde transport mechanistically governs Gli processing unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how IFT43, as the peripheral arm of IFT-A, mechanistically couples retrograde transport to selective GPCR cargo loading and to Gli processing.
  • No structural model of IFT43 within an assembled retrograde train
  • Direct cargo-recognition mechanism for GPCRs beyond EP4 not defined
  • Link between transport defect and Gli activator/repressor balance not mechanistically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 3 GO:0005829 cytosol 2
Pathway
R-HSA-9609507 Protein localization 2 R-HSA-162582 Signal Transduction 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
EP4IFT121IFT139RAB23
Complex memberships
IFT-A complexIFT-A peripheral subcomplex (IFT43/IFT121/IFT139)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 IFT43 is a subunit of the IFT complex A (IFT-A) machinery. A homozygous mutation in the initiation codon of IFT43 (C14ORF179) disrupts translation, producing a shorter protein from a downstream ATG. In patient fibroblasts, loss of IFT43 disrupts retrograde ciliary transport (from ciliary tip to base), causing IFT-B proteins to accumulate at the ciliary tip while anterograde transport remains functional. Western blot (translation effect), immunofluorescence of IFT proteins in ciliated fibroblast cell lines from Sensenbrenner syndrome patients Journal of medical genetics High 21378380
2011 IFT43 directly interacts with IFT121 within the IFT-A complex. IFT43 and IFT121 form the 'peripheral' or 'satellite' subcomplex of IFT-A, distinct from the core IFT144/IFT140/IFT122 subcomplex. A significant fraction of cell-body IFT43 exists as a ~2S species not associated with the full IFT-A complex, suggesting it can exist independently. Yeast two-hybrid analysis, recombinant protein co-expression in E. coli (pulldown), sucrose density gradient centrifugation, antibody pulldowns, analysis of ift121 and ift122 mutants in Chlamydomonas reinhardtii The Journal of biological chemistry High 22170070
2016 IFT43 is part of the peripheral subcomplex of IFT-A (together with IFT121/IFT139), distinct from the core subcomplex (IFT122/IFT140/IFT144). The peripheral subcomplex associates with the core via IFT121-IFT122 interaction. IFT139-knockout cells (peripheral subunit) accumulate IFT-A, IFT-B, and GPCRs (Smoothened, GPR161) at bulged ciliary tips, phenocopying IFT43 peripheral subcomplex disruption, while IFT144-KO (core) blocks ciliary entry of GPCRs. Visible immunoprecipitation (VIP) assay for protein-protein interactions, CRISPR/Cas9 knockout of IFT139 and IFT144 in hTERT-RPE1 cells, immunofluorescence of ciliary GPCRs Molecular biology of the cell High 27932497
2013 The small GTPase Rsg1 is required for appropriate cytoplasmic localization of the retrograde IFT-A protein IFT43 in multiciliated cells. Loss of Rsg1 impairs axonemal IFT dynamics and leads to mislocalization of IFT43. Loss-of-function (morpholino knockdown) in Xenopus multiciliated cells, live imaging of IFT dynamics, immunofluorescence for IFT43 localization Cilia Medium 24192041
2014 IFT43 (tagged with OFP) moves as retrograde IFT particles in primary cilia of mouse renal epithelial (IMCD-3) cells at ~0.45 µm/s, the same velocity as anterograde IFT proteins (KIF3B, IFT20) and BBSome protein BBS8, indicating IFT43 is transported as part of the IFT machinery. Live fluorescence imaging of fluorescently tagged IFT43 (OFP::IFT43) in IMCD-3 cells; velocity measurements PloS one Medium 25243405
2017 In Chlamydomonas, loss of IFT54 (an IFT-B component) causes accumulation of IFT-A component IFT43 (along with IFT-B component IFT46) at the flagellar tip in stunted flagella, indicating IFT54 functions in IFT turnaround at the flagellar tip and that IFT43 tip accumulation is a readout of defective retrograde IFT. Genetic complementation in Chlamydomonas ift54 mutants expressing CC domain alone; immunofluorescence/immunoblot for IFT43 in flagella Cellular and molecular life sciences : CMLS Medium 28417161
2017 Mutations in IFT43 disrupt ciliogenesis in patient-derived cells and produce abnormalities in cartilage growth plate architecture (disordered chondrocyte proliferation and differentiation), contributing to altered endochondral ossification and mineralization. IFT43 is identified as a 'satellite' member of the retrograde IFT-A complex that directly interacts with IFT121. Whole-exome sequencing, histological analysis of cartilage growth plates in SRPS patients, ciliogenesis assay in patient-derived cells Cilia Medium 28400947
2017 A homozygous missense mutation in IFT43 (c.100 G>A) causes recessive retinal degeneration. Mutant IFT43 expression in mIMCD3 and MDCK cells produces significantly shorter cilia compared to wild-type IFT43. IFT43 protein localizes to the tip of cilia in transfected cells and to photoreceptors in the retina. Heterologous expression of wild-type and mutant IFT43 in mIMCD3 and MDCK cells; immunostaining for subcellular localization; cilium length measurement; RT-PCR, western blot, immunohistochemistry Human molecular genetics Medium 28973684
2020 Under simulated microgravity (SMG), the ratio of anterograde (IFT88) to retrograde (IFT43-labeled) IFT particle number increases and IFT particle size decreases in osteocyte cilia, demonstrating that IFT43-labeled retrograde particles can be quantified as a direct readout of retrograde IFT transport in living osteocytes. Live fluorescence imaging of OFP::IFT43 (retrograde) and GFP::IFT88 (anterograde) in osteocytes under simulated microgravity; particle counting and size measurement Biochemical and biophysical research communications Low 32828281
2025 IFT43 physically interacts with the prostaglandin E receptor 4 (EP4) GPCR through EP4's third intracellular loop (IC3) and C-terminal region. IFT43 and Rab23 GTPase cooperate to regulate EP4 trafficking to primary cilia. siRNA knockdown of IFT43 impairs ciliary localization of EP4 in zebrafish and mammalian cells. High-content siRNA screening; co-immunoprecipitation between EP4 and IFT43; domain mapping by deletion constructs; immunofluorescence of EP4 in cilia after IFT43 knockdown in zebrafish and mammalian cells Communications biology Medium 41372612
2026 Loss of Ift43 in mice causes mid-gestation lethality with severe craniofacial defects, exencephaly, and limb patterning defects. At the cellular level, Ift43 deficiency reduces cilia number and length, blocks Gli1 induction after Hedgehog pathway activation (SAG treatment), causes abnormal accumulation of Gli2 and Gli3 at ciliary tips before stimulation, and fails to suppress Gli repressor forms after activation. Ift43 overexpression increases basal Gli2 cleavage into repressor form. Smoothened relocalizes to cilia normally in Ift43 mutants. Conditional/constitutive mouse knockout (Ift43 null); immunofluorescence for Gli2, Gli3, Smoothened in cilia; Hedgehog pathway activation assay (SAG); Gli1 mRNA induction; Ift43 overexpression with Gli2 cleavage assay bioRxivpreprint Medium 41648367
2016 Haploinsufficiency of IFT43 (due to a de novo 14q24.2q24.3 microdeletion) in patient-derived fibroblasts results in increased accumulation of IFT-B proteins at the ciliary tip, demonstrating defective retrograde ciliary transport even with partial IFT43 loss. Immunocytochemistry for IFT-B proteins in fibroblasts from a patient with a heterozygous IFT43 deletion; comparison to control cells American journal of medical genetics. Part A Low 26892345

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Ciliary disorder of the skeleton. American journal of medical genetics. Part C, Seminars in medical genetics 196 22791528
2011 C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. Journal of medical genetics 123 21378380
2016 Intraflagellar transport-A complex mediates ciliary entry and retrograde trafficking of ciliary G protein-coupled receptors. Molecular biology of the cell 120 27932497
2011 Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins. The Journal of biological chemistry 92 22170070
2014 Regulation of cilium length and intraflagellar transport by the RCK-kinases ICK and MOK in renal epithelial cells. PloS one 81 25243405
2018 Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Human molecular genetics 55 29220510
2017 IFT54 regulates IFT20 stability but is not essential for tubulin transport during ciliogenesis. Cellular and molecular life sciences : CMLS 35 28417161
2017 Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia. Cilia 29 28400947
2021 Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia. Human molecular genetics 24 33517396
2020 Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans. Epigenetics 19 33100131
2016 Novel IFT122 mutations in three Argentinian patients with cranioectodermal dysplasia: Expanding the mutational spectrum. American journal of medical genetics. Part A 19 26792575
2013 The Small GTPase Rsg1 is important for the cytoplasmic localization and axonemal dynamics of intraflagellar transport proteins. Cilia 19 24192041
2020 Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease. Orphanet journal of rare diseases 18 32007091
2017 A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Human molecular genetics 16 28973684
2019 Ttc39c is upregulated during skeletal muscle atrophy and modulates ERK1/2 MAP kinase and hedgehog signaling. Journal of cellular physiology 14 31188487
2014 Control elements targeting Tgfb3 expression to the palatal epithelium are located intergenically and in introns of the upstream Ift43 gene. Frontiers in physiology 11 25071603
2023 A whole exome sequencing study to identify rare variants in multiplex families with alcohol use disorder. Frontiers in psychiatry 9 37915799
2020 Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35. American journal of medical genetics. Part A 9 32804427
2020 The microgravity induces the ciliary shortening and an increased ratio of anterograde/retrograde intraflagellar transport of osteocytes. Biochemical and biophysical research communications 8 32828281
2019 A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy. European journal of medical genetics 7 31816441
2017 Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations. Birth defects research 7 29134781
2020 Primary ciliary dyskinesia relative protein ZMYND10 is involved in regulating ciliary function and intraflagellar transport in Paramecium tetraurelia. European journal of protistology 6 33279757
2024 Genetic profiling of azoospermic men to identify the etiology and predict reproductive potential. Journal of assisted reproduction and genetics 4 38403804
2024 Identification of the principal neuropeptide MIP and its action pathway in larval settlement of the echiuran worm Urechis unicinctus. BMC genomics 4 38641568
2016 De novo 14q24.2q24.3 microdeletion including IFT43 is associated with intellectual disability, skeletal anomalies, cardiac anomalies, and myopia. American journal of medical genetics. Part A 3 26892345
2024 Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol. Human genomics 2 39090729
2023 Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with WDR35 variants. Frontiers in molecular biosciences 2 38161384
2023 Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in GRK2: A Newly Associated Gene for Jeune Syndrome Phenotype. Molecular syndromology 2 38585547
2018 [Clinical features and mutational analysis of a case with Sensenbrenner syndrome]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 29896747
2026 Ift43 Controls the Ciliary Levels of Gli2 and Gli3. bioRxiv : the preprint server for biology 0 41648367
2026 IFT43-Related Cranioectodermal Dysplasia Type 3: Clinical and Molecular Insights from the First Reported Turkish Patient. Molecular syndromology 0 42137187
2026 Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal Dysplasia 1 in a Consanguineous Saudi Family. Molecular genetics & genomic medicine 0 42144731
2025 Maternal and Parent-of-Origin Gene-Environment Effects on the Etiology of Orofacial Clefting. Genes 0 40004524
2025 [Two cases of skeletal ciliopathies in one family]. Zeitschrift fur Geburtshilfe und Neonatologie 0 40749718
2025 Rab23 GTPase and IFT43 regulate the trafficking of prostaglandin E receptor 4 to primary cilia. Communications biology 0 41372612
2023 Canonical Wnt signaling is not required for Tgfb3 expression in the basal medial edge epithelium during palatogenesis. Frontiers in physiology 0 37250135

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