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

Autor:	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., 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., 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., 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., 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., Rae J; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., 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., 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., 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., 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., 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., Mahrhold S; Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany., Krez N; Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany., 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., 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., 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., Collins BM; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., 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., Balistreri G; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.; Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Rummel A; Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany., 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.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2023 Jul 03; Vol. 42 (13), pp. e112095. Date of Electronic Publication: 2023 May 25.
DOI:	10.15252/embj.2022112095
Abstrakt:	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. (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze:	MEDLINE
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