Deinhardt Katrin, Berninghausen Otto, Willison Hugh J, Hopkins Colin R, Schiavo Giampietro
Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, England, UK.
J Cell Biol. 2006 Jul 31;174(3):459-71. doi: 10.1083/jcb.200508170.
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.
配体 - 受体复合物通过多种内吞机制内化。一些在内陷蛋白包被的膜内起始，而其他的则涉及质膜的脂质微区。在神经元中，向短程或长程运输途径的选择性靶向是突触小泡成分和神经营养因子受体差异加工的基础，而进入轴突逆行途径的机制仍然未知。为了研究这种分选过程，我们检测了破伤风神经毒素片段（TeNT HC）的内化，它与神经营养因子及其受体共用轴突载体。先前的研究表明，由多唾液酸神经节苷脂组成的TeNT HC受体存在于脂质微区中。我们证明TeNT HC的内化也依赖于一种特殊的网格蛋白介导的途径，该途径独立于突触小泡循环。此外，与转铁蛋白摄取不同，这个依赖AP - 2的过程独立于 epsin1。这些发现确定了TeNT的一条途径，始于与脂筏成分（GD1b）的结合，随后随着毒素通过网格蛋白介导的机制利用特定子集的衔接蛋白内化而与GD1b解离。
