IFT46

IFT46 is a core subunit of intraflagellar transport (IFT) complex B that is essential for ciliogenesis and for the selective import of axonemal cargoes into cilia and flagella (PMID:17312020, PMID:25722189). Its function is structurally bipartite: the C-terminal region (residues 246–321, including L285/L286) docks onto IFT52 to assemble and stabilize the IFT-B core and to drive basal-body and ciliary targeting, such that loss of IFT46 destabilizes most complex B proteins (PMID:17312020, PMID:20435895, PMID:28302912); ectopic nuclear-tethered IFT52 re-routes IFT46 to the nucleus, confirming IFT52 directs IFT46 localization (PMID:28302912). The N-terminal 147 residues are functionally dedicated to cargo handling, binding the cargo adaptor ODA16 with ~200 nM affinity to mediate intraflagellar transport of outer dynein arms—a role genetically separable from the protein's structural role, since an IFT46 fragment that restores complex B stability still cannot import ODA16 or outer dynein arms (PMID:17312020, PMID:28701346, PMID:28298440). IFT46 also participates in an IFT46–IFT56 dimer that binds the homodimeric kinesin KIF17 and licenses its entry into cilia across the ciliary permeability barrier (PMID:28077622). Across organisms IFT46 is required for trafficking of IFT-B proteins between cytoplasm and cilia, and its loss in vertebrates produces shortened or absent cilia and randomized left-right axis patterning (PMID:25722189, PMID:29915351). Beyond ciliogenesis, IFT46 deficiency in renal collecting-duct cells impairs autophagy flux, elevating Limk2 (a p62/SQSTM1 interactor) to promote partial epithelial-to-mesenchymal transition and renal cyst formation (PMID:41680856).

1. 2007 High

   Established that IFT46 is a required structural component of IFT complex B and, separately, that it carries out a specific cargo function for outer dynein arm import—the first evidence that one IFT subunit couples assembly to selective cargo transport.

   Evidence Insertional null mutants and a suppressor that restores complex B without IFT46, with axonemal EM and Western blots in Chlamydomonas

   PMID:17312020

   Open questions at the time

   • Did not map which IFT46 domains mediate structural versus cargo functions
   • Direct cargo adaptor for outer dynein arms not yet identified
2. 2010 High

   Defined the molecular basis of IFT46's structural role by showing it forms a ternary core with IFT88 and IFT52, and localized the assembly determinant to the C-terminus while assigning cargo transport to the N-terminus.

   Evidence Yeast two-hybrid, bacterial co-expression, chemical cross-linking, and electroporation rescue of ift46 mutants

   PMID:20435895

   Open questions at the time

   • Did not identify the N-terminal binding partner mediating dynein arm transport
   • Precise residues contacting IFT52 not yet defined
3. 2017 High

   Resolved how IFT46 selects outer dynein arm cargo: its N-terminal 147 residues bind the cargo adaptor ODA16, and structural work defined the ODA16 architecture (N-terminal domain plus 8-bladed β-propeller) and the ~200 nM affinity of the interaction, linking adaptor binding to ODA recognition.

   Evidence Chlamydomonas suppressor domain dissection plus X-ray crystallography of ODA16, truncation/mutagenesis binding maps, affinity measurement, and Co-IP with axonemal ODAs

   PMID:28298440 PMID:28701346

   Open questions at the time

   • Stoichiometry of the IFT46–ODA16–ODA assembly during transit not resolved
   • How cargo is released at the ciliary tip unknown
4. 2017 High

   Pinpointed the targeting mechanism by showing IFT52 recruits IFT46 to the basal body through L285/L286 in a C-terminal sequence (246–321) that is necessary and sufficient for ciliary localization, with ectopic nuclear IFT52 mislocalizing IFT46.

   Evidence IFT46 truncation/site-directed mutagenesis, Co-IP, motor-mutant epistasis, and ectopic nuclear targeting in Chlamydomonas

   PMID:28302912

   Open questions at the time

   • Whether targeting precedes or follows IFT-B core assembly not resolved
   • Regulation of IFT52–IFT46 docking unknown
5. 2017 Medium

   Extended IFT46's adaptor role beyond dynein arms by showing an IFT46–IFT56 dimer binds KIF17 and is required for KIF17 entry into cilia across the permeability barrier.

   Evidence Visible immunoprecipitation assay, KIF17 C-terminal deletion mapping, and RNAi/rescue in mammalian cells

   PMID:28077622

   Open questions at the time

   • Interaction shown by a single primary method (VIP) from one lab
   • Structural basis of the IFT46–IFT56–KIF17 interaction not defined
6. 2015 Medium

   Demonstrated the physiological requirement for IFT46 in vertebrate ciliogenesis and left-right patterning, generalizing the Chlamydomonas findings to development.

   Evidence Morpholino knockdown in zebrafish and Ift46 knockout mice with IF localization and ciliary EM

   PMID:25722189

   Open questions at the time

   • No molecular mechanism beyond the IFT-B role established in vertebrates
   • Tissue-specific cargo dependencies not dissected
7. 2018 Medium

   Confirmed IFT46's conserved role in shuttling IFT-B proteins between cytoplasm and cilia by showing IFT57 mislocalizes upon IFT46 depletion.

   Evidence RNAi knockdown in Paramecium with GFP-tagged IFT57 fluorescence localization

   PMID:29915351

   Open questions at the time

   • Single organism, single cargo readout
   • Whether IFT46 acts on IFT57 directly or via complex B integrity not distinguished
8. 2026 Medium

   Uncovered a non-ciliary function in which IFT46 deficiency impairs autophagy flux to stabilize Limk2 and drive partial EMT, linking IFT46 loss to renal cyst formation.

   Evidence RNA-seq, Limk2–p62 Co-IP, 3D cyst culture, collecting-duct-specific Ift46 knockout mice, and autophagy flux assays, with human ADPKD validation

   PMID:41680856

   Open questions at the time

   • Co-IP for Limk2–p62 without reciprocal/structural validation
   • How IFT46 mechanistically controls autophagy flux not defined
   • Novel axis not yet independently replicated

• How IFT46's ciliary transport function mechanistically connects to its regulation of autophagy and Limk2 stability remains unresolved.
• Whether the autophagy phenotype is a direct IFT46 activity or a downstream consequence of cilia loss is unknown
• No structural model of the IFT46 N-terminus bound to ODA16 in the full IFT-B context
• Mechanism of cargo loading and release during transit not defined