title: Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1.
abstract: Ligand-receptor complexes are internalized by a variety of endocytic mechanisms. Some are initiated within clathrin-coated membranes, whereas others involve lipid microdomains of the plasma membrane. In neurons, where alternative targeting to short- or long-range trafficking routes underpins the differential processing of synaptic vesicle components and neurotrophin receptors, the mechanism giving access to the axonal retrograde pathway remains unknown. To investigate this sorting process, we examined the internalization of a tetanus neurotoxin fragment (TeNT HC), which shares axonal carriers with neurotrophins and their receptors. Previous studies have shown that the TeNT HC receptor, which comprises polysialogangliosides, resides in lipid microdomains. We demonstrate that TeNT HC internalization also relies on a specialized clathrin-mediated pathway, which is independent of synaptic vesicle recycling. Moreover, unlike transferrin uptake, this AP-2-dependent process is independent of epsin1. These findings identify a pathway for TeNT, beginning with the binding to a lipid raft component (GD1b) and followed by dissociation from GD1b as the toxin internalizes via a clathrin-mediated mechanism using a specific subset of adaptor proteins.
authors.affiliation: Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, England, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Deinhardt
authors.forename: Otto
authors.initials: O
authors.lastname: Berninghausen
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
authors.forename: Colin R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D034001:Adaptor Protein Complex Subunits / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism* / Q000648:ultrastructure; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism / Q000648:ultrastructure; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D005089:Exocytosis; D005732:Gangliosides / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D008954:Models, Biological; D009046:Motor Neurons / Q000166:cytology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000378:metabolism; D021381:Protein Transport; D013572:Synaptic Vesicles / Q000648:ultrastructure; D013744:Tetanus Toxin / Q000378:metabolism*
chemical_list: D034001:Adaptor Protein Complex Subunits; D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; D005732:Gangliosides; D010446:Peptide Fragments; D013744:Tetanus Toxin; C114154:epsin; C040635:tetanus toxin fragment C; C033851:ganglioside, GD1b; D034281:Dynamins