Botulinum Neurotoxin D Uses Synaptic Vesicle Protein SV2 and Gangliosides as Receptors

PLoS Pathogens

Eric A. Johnson¹  William H. Tepp¹  Min Dong²  Lisheng Peng² 

[1] Department of Food Microbiology and Toxicology, University of Wisconsin, Madison, Wisconsin, United States of America;Department of Microbiology and Molecular Genetics, Harvard Medical School and Division of Neuroscience, New England Primate Research Center, Southborough, Massachusetts, United States of America

关键词: Neurons;    Toxins;    Sphingolipids;    Immunostaining;    Synaptic vesicles;    Membrane proteins;    Cell binding;    Cell membranes;   

DOI  :  10.1371/journal.ppat.1002008

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Botulinum neurotoxins (BoNTs) include seven bacterial toxins (BoNT/A-G) that target presynaptic terminals and act as proteases cleaving proteins required for synaptic vesicle exocytosis. Here we identified synaptic vesicle protein SV2 as the protein receptor for BoNT/D. BoNT/D enters cultured hippocampal neurons via synaptic vesicle recycling and can bind SV2 in brain detergent extracts. BoNT/D failed to bind and enter neurons lacking SV2, which can be rescued by expressing one of the three SV2 isoforms (SV2A/B/C). Localization of SV2 on plasma membranes mediated BoNT/D binding in both neurons and HEK293 cells. Furthermore, chimeric receptors containing the binding sites for BoNT/A and E, two other BoNTs that use SV2 as receptors, failed to mediate the entry of BoNT/D suggesting that BoNT/D binds SV2 via a mechanism distinct from BoNT/A and E. Finally, we demonstrated that gangliosides are essential for the binding and entry of BoNT/D into neurons and for its toxicity in vivo, supporting a double-receptor model for this toxin.

【 授权许可】

CC BY