IFT46

IFT46 is a core subunit of the intraflagellar transport complex B (IFT-B) that is essential for ciliogenesis, ciliary cargo delivery, and cilium-dependent developmental signaling. Its C-terminal domain (residues 246–321, including L285/L286) mediates direct binding to IFT52 for basal body targeting and IFT-B complex assembly/stability, while its N-terminal domain (residues 1–147) binds the cargo adaptor ODA16 (Kd ~200 nM) to specifically transport outer dynein arms into cilia; IFT46 also forms a ternary complex with IFT52 and IFT88, and its dimer interface with IFT56 is required for KIF17 ciliary entry (PMID:17312020, PMID:20435895, PMID:28298440, PMID:28077622, PMID:28302912). Loss of IFT46 in vertebrates causes kidney cysts, left-right patterning defects, and shortened cilia, and SARS-CoV-2 ORF10 hijacks the CUL2^ZYG11B E3 ligase to ubiquitinate and degrade IFT46, impairing ciliary biogenesis and maintenance (PMID:25722189, PMID:35674692). IFT46 also regulates autophagy flux in kidney collecting duct cells, where its deficiency stabilizes Limk2 to promote partial epithelial-to-mesenchymal transition and renal cyst formation (PMID:41680856).

1. 2007 High

   Establishing that IFT46 is a core IFT-B subunit required both for complex B stability/flagellar assembly and specifically for outer dynein arm transport resolved whether individual IFT-B proteins have cargo-selective roles beyond structural scaffolding.

   Evidence Insertional mutagenesis and suppressor genetics in Chlamydomonas with Western blot and EM readouts

   PMID:17312020

   Open questions at the time

   • Direct binding partners within IFT-B were not identified
   • Mechanism by which IFT46 recognizes outer dynein arms was unknown
   • Vertebrate developmental roles had not been tested
2. 2007 Medium

   Demonstrating IFT46 localization to primary cilia of mammalian chondrocytes and its regulation by BMP-2 extended IFT46 function from Chlamydomonas to vertebrate developmental signaling contexts.

   Evidence Immunofluorescence localization in mouse chondrocytes, siRNA knockdown gene expression analysis, zebrafish morpholino injection

   PMID:17720815

   Open questions at the time

   • Single lab with antibody-based localization; independent confirmation lacking at that time
   • Mechanism linking IFT46 to skeletogenesis gene regulation was not elucidated
3. 2010 High

   Identifying IFT46 as forming a direct ternary complex with IFT52 and IFT88 defined the core IFT-B architecture and showed these three subunits constitute a minimal IFT-B assembly unit.

   Evidence Yeast two-hybrid, bacterial co-expression, chemical cross-linking, electroporation rescue and live imaging in Chlamydomonas

   PMID:20435895

   Open questions at the time

   • Atomic-resolution structure of the ternary complex was not available
   • Relative contributions of IFT52 versus IFT88 binding to IFT46 stability were unclear
4. 2015 High

   Knockout and knockdown studies in zebrafish and mouse proved IFT46 is essential for vertebrate ciliogenesis and left-right axis patterning, establishing it as a ciliopathy-relevant gene.

   Evidence Morpholino knockdown in zebrafish and Ift46 knockout mouse generation with EM, immunofluorescence, and developmental phenotyping

   PMID:25722189

   Open questions at the time

   • No human ciliopathy mutations in IFT46 had been identified
   • Whether specific cilia subtypes have differential IFT46 dependence was untested
5. 2017 High

   Structural and biochemical dissection of the IFT46–ODA16 interaction revealed that the IFT46 N-terminus (residues 1–147) binds ODA16's β-propeller domain with ~200 nM affinity, while ODA16 separately contacts outer dynein arms, establishing the architectural basis for cargo-selective IFT.

   Evidence X-ray crystallography of ODA16, ITC binding measurements, pulldown with axonemal ODAs, deletion mutagenesis in Chlamydomonas

   PMID:28298440 PMID:28701346

   Open questions at the time

   • Atomic structure of the IFT46–ODA16 binary complex was not resolved
   • Whether other cargo adaptors bind a similar IFT46 surface was unknown
6. 2017 High

   Mapping the IFT46 C-terminal BBTS3 domain (residues 246–321) and the critical L285/L286 residues for IFT52 binding revealed that IFT52–IFT46 preassembly in the cytoplasm is required for basal body targeting, separating complex assembly from cargo-loading functions.

   Evidence Truncation mapping, site-directed mutagenesis, motor/IFT mutant analysis, and fluorescence microscopy in Chlamydomonas

   PMID:28302912

   Open questions at the time

   • Structural basis for IFT52–IFT46 BBTS3 interaction was not determined at atomic resolution
   • Cytoplasmic versus basal body assembly sequence for the full IFT-B complex remained incomplete
7. 2017 High

   Discovery that the IFT46–IFT56 dimer provides the binding interface for KIF17 ciliary entry revealed a second cargo/motor-adaptor role for IFT46 distinct from its ODA16-binding function.

   Evidence Visible immunoprecipitation assay, deletion mutagenesis, live-cell imaging, and ciliary entry assays in mammalian cells

   PMID:28077622

   Open questions at the time

   • Whether IFT46–IFT56 binding to KIF17 is regulated remains unknown
   • Functional consequence of disrupting KIF17–IFT46 interaction on specific ciliary signaling pathways was not determined
8. 2022 High

   Demonstrating that SARS-CoV-2 ORF10 hijacks CUL2^ZYG11B to ubiquitinate and degrade IFT46, impairing cilia biogenesis and maintenance, identified a viral mechanism for disrupting mucociliary clearance.

   Evidence Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, hACE2 mouse model, primary human nasal epithelial cell culture

   PMID:35674692

   Open questions at the time

   • The specific ubiquitination sites on IFT46 were not mapped
   • Whether other IFT-B subunits are co-degraded or destabilized secondarily was not fully addressed
   • Clinical relevance for COVID-19 airway pathology requires further patient-level evidence
9. 2026 Medium

   Identifying that IFT46 regulates autophagy flux to control Limk2 stability and partial EMT in kidney collecting duct cells uncovered a non-canonical, cilia-independent function linked to cystic kidney disease.

   Evidence RNA-seq, co-immunoprecipitation, conditional knockout mice, 3D cyst culture model, autophagy-modulating drugs, human ADPKD tissue analysis

   PMID:41680856

   Open questions at the time

   • Single-lab finding; independent replication of the IFT46–autophagy–Limk2 axis is needed
   • Mechanism by which IFT46 controls autophagy flux is not defined
   • Whether the autophagy role is fully independent of cilia or partially coupled remains unclear

• Key unresolved questions include the atomic structure of the IFT46–ODA16 binary complex, whether IFT46 has additional non-ciliary functions in other tissues, and whether human IFT46 mutations cause a defined ciliopathy.
• No human disease-causing mutations in IFT46 have been reported
• Full reconstitution of IFT46-dependent cargo loading onto IFT trains has not been achieved
• The autophagy-regulatory mechanism of IFT46 at the molecular level is undefined