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<p>Botulinum neurotoxins (BoNT) are the most potent protein toxins for humans, yet how BoNT-Light Chain/A1 (LC/A1) journeys to cleave intracellular SNAP-25 is understudied. Here we use a cell-based assay to measure cytosolic EGFP-LC/A1 intracellular trafficking and SNAP-25 cleavage in Neuro-2A cells. Intracellular LC/A1 associated on microtubules and co-localized with Rab GTPases involved in fast synaptic vesicles and endosome recycling. Multiple Dominant Negative (DN) Rabs GTPases involved in fast synaptic vesicles or endosome recycling inhibited LC/A1 trafficking to the intracellular plasma membrane and SNAP-25 cleavage. A cytosolic LC/A1 variant that bound the plasma membrane from the cytosol was insensitive to DNRab GTPases involved in fast synaptic vesicle recycling. LC/A1 traffics on fast synaptic vesicles to the intracellular plasma membrane to cleave SNAP-25. Our data suggest, like Heavy Chain host cell entry and LC catalysis, LC intracellular trafficking to target host substrates can contribute to bacterial toxin potency.</p>

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Botulinum neurotoxin Light Chain/A1 uses fast synaptic vesicle cycling to cleave plasma membrane bound SNAP-25

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Alexander Gardner,
  • Molly Sneller,
  • William H. Tepp,
  • Joseph T. Barbieri,
  • Sabine Pellett

摘要

Botulinum neurotoxins (BoNT) are the most potent protein toxins for humans, yet how BoNT-Light Chain/A1 (LC/A1) journeys to cleave intracellular SNAP-25 is understudied. Here we use a cell-based assay to measure cytosolic EGFP-LC/A1 intracellular trafficking and SNAP-25 cleavage in Neuro-2A cells. Intracellular LC/A1 associated on microtubules and co-localized with Rab GTPases involved in fast synaptic vesicles and endosome recycling. Multiple Dominant Negative (DN) Rabs GTPases involved in fast synaptic vesicles or endosome recycling inhibited LC/A1 trafficking to the intracellular plasma membrane and SNAP-25 cleavage. A cytosolic LC/A1 variant that bound the plasma membrane from the cytosol was insensitive to DNRab GTPases involved in fast synaptic vesicle recycling. LC/A1 traffics on fast synaptic vesicles to the intracellular plasma membrane to cleave SNAP-25. Our data suggest, like Heavy Chain host cell entry and LC catalysis, LC intracellular trafficking to target host substrates can contribute to bacterial toxin potency.