Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry.

Botulinum Toxins, Type A / metabolism Cell Membrane / metabolism Membrane Glycoproteins / genetics Nerve Tissue Proteins / metabolism Synaptic Vesicles / metabolism Animals Rats
BoNT/A SV2 endocytosis polysialogianglioside synaptotagmin-1

Journal

The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664

Informations de publication

Date de publication:
03 07 2023
Historique:
revised: 18 04 2023
received: 11 07 2022
accepted: 28 04 2023
medline: 30 6 2023
pubmed: 25 5 2023
entrez: 25 5 2023
Statut: ppublish

Résumé

The unique nerve terminal targeting of botulinum neurotoxin type A (BoNT/A) is due to its capacity to bind two receptors on the neuronal plasma membrane: polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Whether and how PSGs and SV2 may coordinate other proteins for BoNT/A recruitment and internalization remains unknown. Here, we demonstrate that the targeted endocytosis of BoNT/A into synaptic vesicles (SVs) requires a tripartite surface nanocluster. Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wildtype and receptor-binding-deficient mutants in cultured hippocampal neurons demonstrated that BoNT/A must bind coincidentally to a PSG and SV2 to target synaptic vesicles. We reveal that BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) complex and SV2 on the neuronal plasma membrane, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting of the toxin into synaptic vesicles. Syt1 CRISPRi knockdown suppressed BoNT/A- and BoNT/E-induced neurointoxication as quantified by SNAP-25 cleavage, suggesting that this tripartite nanocluster may be a unifying entry point for selected botulinum neurotoxins that hijack this for synaptic vesicle targeting.

Identifiants

DOI: 10.15252/embj.2022112095 PMID: 37226896 PMC: PMC10308369
pubmed: 37226896
doi: 10.15252/embj.2022112095
pmc: PMC10308369
doi:

Substances chimiques

Botulinum Toxins, Type A EC 3.4.24.69
Membrane Glycoproteins 0
Nerve Tissue Proteins 0
trisialoganglioside GT1 59247-13-1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e112095

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

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Auteurs

Merja Joensuu (M)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-4533-0455

Parnayan Syed (P)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0001-7025-7037

Saber H Saber (SH)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0003-1296-2023

Vanessa Lanoue (V)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-2572-1774

Tristan P Wallis (TP)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.

James Rae (J)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Ailisa Blum (A)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0003-4666-9255

Rachel S Gormal (RS)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0003-1604-0253

Christopher Small (C)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.

Shanley Sanders (S)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.

Anmin Jiang (A)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-7495-1875

Stefan Mahrhold (S)

Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.

Nadja Krez (N)

Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.

Michael A Cousin (MA)

Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.
Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0002-1762-160X

Ruby Cooper-White (R)

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
School of Chemical Engineering, The University of Queensland, Brisbane, QLD, Australia.

Justin J Cooper-White (JJ)

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
School of Chemical Engineering, The University of Queensland, Brisbane, QLD, Australia.
UQ Centre for Stem Cell Ageing and Regenerative Engineering, The University of Queensland, Brisbane, QLD, Australia.

Brett M Collins (BM)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-6070-3774

Robert G Parton (RG)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0002-7494-5248

Giuseppe Balistreri (G)

Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Andreas Rummel (A)

Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany.
ORCID: 0000-0002-0645-1641

Frédéric A Meunier (FA)

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
ORCID: 0000-0001-6400-1107

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Classifications MeSH

Recherchemedicale.com › Facteurs biologiques › Toxines biologiques › Toxines bactériennes › Toxines botuliniques › Toxines botuliniques de type A › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Cellules › Structures cellulaires › Membrane cellulaire › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Glycoprotéines membranaires › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Vésicules de transport › Vésicules de sécrétion › Vésicules synaptiques › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Eucaryotes › Animaux › Presynaptic targeting of botulinum neurotoxin...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Presynaptic targeting of botulinum neurotoxin...