YIF1B

YIF1B is an intermediate compartment (IC)-resident scaffold protein that regulates anterograde ER-to-Golgi trafficking by assembling cargo-containing vesicular complexes with Yip1A, Rab6, and the kinesin motor Kif5B, thereby directing specific transmembrane proteins to their correct subcellular destinations (PMID:23055492, PMID:26077767). YIF1B engages cargo through its transmembrane domain, binding the C-terminal tribasic motif of the serotonin 5-HT1A receptor with nanomolar affinity and the TMD0 of the lysosomal transporter TAPL via a salt-bridge-dependent mechanism, and also translocates unglycosylated SARS-CoV-2 ORF8 into vesicles for unconventional secretion (PMID:23055492, PMID:30877195, PMID:39811650). Loss of YIF1B disrupts Golgi architecture, causes primary cilia defects, impairs serotonergic neurotransmission with loss of 5-HT1A autoreceptor function and antidepressant responsiveness, and in humans biallelic loss-of-function mutations produce a neurodevelopmental syndrome linking Golgipathies to ciliopathies (PMID:26077767, PMID:33103737, PMID:32459080).

1. 2008 High

   Identifying YIF1B as a direct interactor of the 5-HT1A receptor C-tail established it as a trafficking factor required for somatodendritic receptor sorting, answering how 5-HT1AR reaches dendrites selectively.

   Evidence Yeast two-hybrid, GST pull-down from rat brain, and siRNA knockdown in primary neurons showing selective loss of dendritic 5-HT1AR

   PMID:18685031

   Open questions at the time

   • Binding domain on YIF1B not mapped
   • Mechanism by which YIF1B selects 5-HT1AR over other dendritic receptors unknown
   • No in vivo validation of dendritic targeting defect
2. 2012 High

   Defining the tribasic motif–YIF1B interaction at nanomolar affinity and identifying the Yip1A/Rab6/Kif5B vesicular complex resolved the molecular mechanism by which YIF1B scaffolds cargo for microtubule-based dendritic transport.

   Evidence Surface plasmon resonance (KD ~37 nM), directed mutagenesis, live videomicroscopy of co-trafficking vesicles in neurons

   PMID:23055492

   Open questions at the time

   • Structural basis of scaffold assembly not resolved
   • Whether Rab6 or Kif5B bind YIF1B directly or via Yip1A unclear
   • Stoichiometry of the vesicular complex unknown
3. 2015 High

   Localizing YIF1B to the intermediate compartment and showing that its loss accelerates anterograde but not retrograde traffic — while disorganizing Golgi ultrastructure — established YIF1B as a rate-limiting regulator of ER-to-Golgi transport rather than a general trafficking factor.

   Evidence VSVG and ShTx directional trafficking assays in HeLa cells and KO neurons; electron microscopy of KO mouse CA1 neurons

   PMID:26077767

   Open questions at the time

   • How accelerated anterograde flow leads to Golgi disorganization is mechanistically unclear
   • Whether YIF1B acts as a checkpoint or a sorting factor at the IC not distinguished
4. 2019 Medium

   Demonstrating that YIF1B engages TAPL's TMD0 via a transmembrane salt bridge broadened YIF1B's cargo repertoire beyond GPCRs and revealed transmembrane domain–mediated recognition as a general cargo-binding mechanism.

   Evidence Mass spectrometry interactome, co-immunoprecipitation, RUSH synchronized trafficking assay, siRNA knockdown

   PMID:30877195

   Open questions at the time

   • Single study for TAPL interaction; independent replication pending
   • Whether the TMD-based and C-tail-based cargo recognition modes are mutually exclusive or simultaneous unknown
   • Functional consequence of impaired TAPL trafficking on lysosomal peptide transport not tested
5. 2020 Medium

   Linking biallelic YIF1B loss-of-function in humans and KO mice to primary cilia defects and Golgi disorganization established YIF1B deficiency as a Golgipathy-ciliopathy and connected intracellular trafficking to cilia maintenance, while parallel work showed KO mice have impaired 5-HT1A autoreceptor function, reduced serotonergic innervation, and loss of SSRI responsiveness.

   Evidence Patient fibroblasts plus KO mouse cilia/brain EM and MRI (PMID:33103737); KO mouse autoradiography, behavioral assays, fluoxetine challenge (PMID:32459080)

   PMID:32459080 PMID:33103737

   Open questions at the time

   • Both are single studies; replication in independent cohorts needed
   • Molecular pathway from Golgi disorganization to cilia defects not delineated
   • Whether 5-HT1AR mistrafficking fully accounts for the behavioral phenotype unclear
6. 2024 Medium

   Identifying YIF1B as the translocator that loads unglycosylated SARS-CoV-2 ORF8 into unconventional secretory vesicles revealed an unexpected role for YIF1B in unconventional protein secretion and viral pathogenesis.

   Evidence Mass spectrometry, domain interaction mapping (α4 helix/β8 sheet), KO/KD in cell and hamster models with inflammatory and survival readouts

   PMID:39811650

   Open questions at the time

   • Single study; mechanism of translocation across the vesicle membrane not resolved
   • Whether YIF1B mediates unconventional secretion of endogenous substrates unknown
   • Generalizability to other viral proteins not tested

• A structural model of YIF1B — alone and in complex with its cargoes and scaffold partners — is needed to unify the dual cargo-recognition modes (C-tail tribasic motif vs. TMD-based) and to explain how YIF1B gates anterograde trafficking at the intermediate compartment.
• No high-resolution structure of YIF1B available
• Full repertoire of endogenous cargo beyond 5-HT1AR and TAPL unknown
• Whether YIF1B plays a general role in unconventional secretion remains untested