Botulinum toxin intoxication requires retrograde transport and membrane translocation at the ER in RenVM neurons.
| Autor: | Yeo JC; Institute of Molecular and Cell Biology, Singapore, Singapore., Tay FP; Institute of Molecular and Cell Biology, Singapore, Singapore., Bennion R; Centre de Recherche en Cancérologie de Marseille, Aix Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes, Equipe Leader Fondation ARC 2021, Marseille, France., Loss O; Ipsen Bioinnovation, London, United Kingdom., Maignel J; Ipsen Innovation, Les Ulis, France., Pons L; Ipsen Innovation, Les Ulis, France., Foster K; Ipsen Bioinnovation, London, United Kingdom., Beard M; Ipsen Bioinnovation, London, United Kingdom., Bard F; Institute of Molecular and Cell Biology, Singapore, Singapore.; Centre de Recherche en Cancérologie de Marseille, Aix Marseille Université, Inserm, CNRS, Institut Paoli-Calmettes, Equipe Leader Fondation ARC 2021, Marseille, France. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2024 Aug 28; Vol. 12. Date of Electronic Publication: 2024 Aug 28. |
| DOI: | 10.7554/eLife.92806 |
| Abstrakt: | Botulinum neurotoxin A (BoNT/A) is a highly potent proteolytic toxin specific for neurons with numerous clinical and cosmetic uses. After uptake at the synapse, the protein is proposed to translocate from synaptic vesicles to the cytosol through a self-formed channel. Surprisingly, we found that after intoxication proteolysis of a fluorescent reporter occurs in the neuron soma first and then centrifugally in neurites. To investigate the molecular mechanisms at play, we use a genome-wide siRNA screen in genetically engineered neurons and identify over three hundred genes. An organelle-specific split-mNG complementation indicates BoNT/A traffic from the synapse to the soma-localized Golgi in a retromer-dependent fashion. The toxin then moves to the ER and appears to require the Sec61 complex for retro-translocation to the cytosol. Our study identifies genes and trafficking processes hijacked by the toxin, revealing a new pathway mediating BoNT/A cellular toxicity. Competing Interests: JY, FT, RB No competing interests declared, OL, KF former employee of Ipsen, JM, LP, MB employee of Ipsen, FB Reviewing editor, eLife (© 2023, Yeo et al.) |
| Databáze: | MEDLINE |
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