Title |
Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG‐Syt1‐SV2 plasma membrane nanocluster for synaptic vesicle entry
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Published in |
EMBO Journal, May 2023
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DOI | 10.15252/embj.2022112095 |
Pubmed ID | |
Authors |
Merja Joensuu, Parnayan Syed, Saber H Saber, Vanessa Lanoue, Tristan P Wallis, James Rae, Ailisa Blum, Rachel S Gormal, Christopher Small, Shanley Sanders, Anmin Jiang, Stefan Mahrhold, Nadja Krez, Michael A Cousin, Ruby Cooper‐White, Justin J Cooper‐White, Brett M Collins, Robert G Parton, Giuseppe Balistreri, Andreas Rummel, Frédéric A Meunier |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 9 | 20% |
Australia | 9 | 20% |
United Kingdom | 3 | 7% |
India | 2 | 4% |
Iran, Islamic Republic of | 1 | 2% |
Virgin Islands, British | 1 | 2% |
Finland | 1 | 2% |
Germany | 1 | 2% |
Netherlands | 1 | 2% |
Other | 2 | 4% |
Unknown | 16 | 35% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 31 | 67% |
Scientists | 11 | 24% |
Science communicators (journalists, bloggers, editors) | 2 | 4% |
Practitioners (doctors, other healthcare professionals) | 2 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 12 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 2 | 17% |
Student > Ph. D. Student | 1 | 8% |
Unspecified | 1 | 8% |
Student > Doctoral Student | 1 | 8% |
Student > Master | 1 | 8% |
Other | 0 | 0% |
Unknown | 6 | 50% |
Readers by discipline | Count | As % |
---|---|---|
Philosophy | 1 | 8% |
Unspecified | 1 | 8% |
Agricultural and Biological Sciences | 1 | 8% |
Immunology and Microbiology | 1 | 8% |
Neuroscience | 1 | 8% |
Other | 0 | 0% |
Unknown | 7 | 58% |