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Published 31 July 2006. doi:10.1083/jcb.200508170
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 3, 459-471
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Article

 Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1

Katrin Deinhardt1, Otto Berninghausen2, Hugh J. Willison3, Colin R. Hopkins2, and Giampietro Schiavo1

1 Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, England, UK
2 Department of Biological Sciences, Imperial College London, London SW7 2AZ, England, UK
3 Division of Clinical Neurosciences, Southern General Hospital, Glasgow G51 4TF, Scotland, UK

Correspondence to Giampietro Schiavo: Giampietro.Schiavo{at}cancer.org.uk

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.

K. Deinhardt and O. Berninghausen contributed equally to this work.

Abbreviations used in this paper: BoNT, botulinum neurotoxin; CCP, clathrin-coated pit; CCV, clathrin-coated vesicle; CHC, clathrin heavy chain; CLC, clathrin light chain; CTB, cholera toxin subunit B; DRM, detergent-resistant membrane; GPI, glycosylphosphatidylinositol; MESNA, 2-mercaptoethane sulfonic acid; MN, motor neuron; NMJ, neuromuscular junction; SV, synaptic vesicles; TeNT HC, tetanus neurotoxin fragment.


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