IFT52

IFT52 is a central scaffolding subunit of the intraflagellar transport IFT-B core complex that is essential for anterograde transport into cilia and for ciliogenesis (PMID:20435895, PMID:25349261). Within the ~500 kDa IFT-B core, IFT52 directly binds IFT88 and IFT46 to form a ternary unit (PMID:20435895), and crystal structures show that its C-terminal segments are buried within the IFT70 TPR superhelix (residues 330–370) and engage IFT88 (residues 281–329), while the IFT52C/IFT46C subcomplex bridges the IFT88/70/52/46 and IFT81/74/27/25/22 subcomplexes to hold the holocomplex together (PMID:25349261). IFT52 docks at the transitional fibers around the basal body, identifying these structures as the entry site for IFT particles, and recruits IFT46 to the basal body through a cytoplasmic preassembly step (PMID:11676918, PMID:28302912). Loss or mutation of IFT52 destabilizes partner subunits, prevents IFT-B holocomplex assembly and its interaction with kinesin-II, and impairs ciliary delivery of cargoes such as ICK/CILK1 and KIF17, manifesting in humans as short-rib polydactyly syndrome (PMID:27466190, PMID:35704471). Beyond the cilium, IFT52 acts upstream of Hedgehog signaling to permit osteogenic differentiation (PMID:35839863) and has an extra-ciliary role at the distal centriole, where it interacts with centrin and prevents centriole splitting (PMID:31042281).

1. 2001 High

   Establishing where IFT particles enter the cilium was unresolved; localizing IFT52 to transitional fibers identified the docking site for IFT particle entry and linked the gene to flagellar assembly via the bld1 null mutant.

   Evidence Immunoelectron microscopy and immunofluorescence with genetic mutant (bld1) analysis in Chlamydomonas

   PMID:11676918

   Open questions at the time

   • Did not define the molecular interactions anchoring IFT52 to transitional fibers
   • Did not establish IFT52's position within the IFT-B complex
2. 2010 High

   How IFT52 fits into the IFT-B core was unknown; orthogonal biochemistry showed it directly binds IFT88 and IFT46 to form a ternary complex within the IFT-B core, defining IFT52 as a core scaffolding subunit.

   Evidence Yeast two-hybrid, bacterial coexpression, chemical cross-linking, and biochemical fractionation

   PMID:20435895

   Open questions at the time

   • No structural detail on the binding interfaces
   • Did not address how the core links to the rest of the IFT-B complex
3. 2014 High

   The structural logic of how IFT52 organizes the IFT-B core was unknown; crystal structures of IFT70/52 and IFT52/46 plus reconstitution showed IFT52 segments thread through IFT70 and IFT88 and that IFT52C/IFT46C bridges the two halves of the core, with dominant-negative IFT52C disrupting ciliogenesis.

   Evidence X-ray crystallography (2.5/2.3 Å), in vitro reconstitution of nonameric IFT-B core, dominant-negative overexpression in MDCK cells

   PMID:25349261

   Open questions at the time

   • Did not address basal body recruitment mechanism
   • Did not test relevance of these interfaces to human disease alleles
4. 2016 Medium

   Whether IFT52 dysfunction causes human disease was open; patient cell studies linked compound heterozygous IFT52 mutations to short-rib polydactyly syndrome through destabilization of IFT-B partners and impaired ciliogenesis.

   Evidence Patient cell western blotting, immunofluorescence cilia quantification, whole-exome sequencing

   PMID:27466190

   Open questions at the time

   • Single lab and patient cohort
   • Did not resolve which molecular interaction each mutation disrupts
5. 2017 High

   How IFT46 reaches the basal body was unclear; truncation, ectopic targeting, and point-mutagenesis assays showed IFT52 recruits IFT46 via specific residues and that the two preassemble in the cytoplasm before basal body targeting.

   Evidence Truncation constructs and ectopic nuclear targeting in ift46-1 Chlamydomonas, genetic epistasis, site-directed mutagenesis

   PMID:28302912

   Open questions at the time

   • Mechanism anchoring the IFT52-IFT46 complex at the basal body not defined
   • Generality to mammalian cells not tested in this study
6. 2018 High

   The contribution of IFT70 to IFT52-dependent ciliogenesis was unresolved; KO/rescue with deletion mutants showed IFT70 binds the IFT52-IFT88 dimer through its first TPR and C-terminal helix, and this interaction is required for ciliogenesis.

   Evidence CRISPR/Cas9 knockout, rescue, deletion mutagenesis, co-immunoprecipitation, immunofluorescence

   PMID:29654116

   Open questions at the time

   • Did not address whether this interface is affected in disease
   • Functional consequences beyond ciliogenesis not examined
7. 2019 Medium

   Whether IFT52 has roles outside the cilium was unknown; co-IP and co-localization revealed an extra-ciliary interaction with centrin at the distal centriole that prevents centriole splitting, alongside an SRTD missense allele impairing IFT-B2 ciliary localization.

   Evidence Co-immunoprecipitation, co-localization, zebrafish in vivo assays, patient cells with Ift52 knockout

   PMID:31042281

   Open questions at the time

   • Centrin-IFT52 interaction shown by co-IP without structural detail
   • Mechanism linking centrin maintenance to centriole cohesion unresolved
8. 2022 Medium

   The molecular basis by which SRPS IFT52 variants impair cilia was unclear; KO-rescue with variant alleles showed they fail to assemble the IFT-B holocomplex and to bind kinesin-II, impairing anterograde delivery of ICK/CILK1 and KIF17.

   Evidence IFT52-KO cells expressing SRPS variants, co-IP for kinesin-II, ciliary tip localization assays

   PMID:35704471

   Open questions at the time

   • Single lab
   • Direct structural mapping of kinesin-II contact not provided
9. 2022 Medium

   The relevance of IFT52 to differentiation signaling was untested; shRNA knockdown placed IFT52 upstream of Hedgehog signaling, with its loss blocking primary ciliogenesis and osteogenic differentiation only partially rescued by Hedgehog activation.

   Evidence Lentiviral shRNA knockdown, osteogenic differentiation assay, Hedgehog activation with SAG, immunofluorescence

   PMID:35839863

   Open questions at the time

   • Incomplete rescue indicates additional cilia-dependent inputs not identified
   • Single cell-type model
10. 2025 Medium

    Whether IFT subunits directly modulate mitotic motors was unknown; in vitro reconstitution showed an IFT52/IFT70 subcomplex directly binds and oligomerizes HSET, generating processive microtubule-sliding complexes that support centrosome clustering.

    Evidence In vitro reconstitution with purified proteins, TIRF microscopy, microtubule sliding assay (preprint)

    PMID:bio_10.1101_2025.01.13.632783

    Open questions at the time

    • Preprint, not yet peer-reviewed
    • In-cell relevance to centrosome clustering not demonstrated biochemically
11. 2025 Low

    Whether external regulators tune IFT52 transport was unexplored; imaging in C. elegans and mouse/human photoreceptors showed CFH mutation slows and mislocalizes IFT52/OSM-6 specifically within IFT-B1, without affecting IFT88.

    Evidence Live imaging of IFT dynamics in C. elegans, immunofluorescence in mouse/human photoreceptors, genetic mutants (preprint)

    PMID:41278837

    Open questions at the time

    • Preprint with imaging-based, indirect epistasis and no biochemical CFH-IFT52 link
    • Mechanism of subcomplex-specific regulation unknown
12. 2026 Low

    Whether IFT52 controls membrane-protein cargo stability was open; immunolocalization in ift52 mutant Chlamydomonas indicated IFT52 (with IFT88) is required for stability and flagellar trafficking of Chlamyopsin6.

    Evidence Immunocytochemistry in IFT-defective Chlamydomonas strains, co-IP (IFT20-Chlamyopsin6)

    PMID:42214917

    Open questions at the time

    • IFT52 role inferred from mutant phenotype without direct interaction
    • Single co-IP only for the IFT20 partner, not IFT52

• How IFT52's extra-ciliary activities (distal centriole centrin maintenance, HSET-dependent centrosome clustering) are mechanistically coordinated with its core IFT-B scaffolding role, and how these are regulated in cells, remains open.
• No structural model of the IFT52-centrin interaction
• In-cell validation of the IFT52/IFT70-HSET mechanism lacking
• Regulatory inputs governing IFT52 partitioning between ciliary and centriolar pools unknown