ArticleNature structural & molecular biology2025
Botulinum neurotoxins exploit host digestive proteases to boost their oral toxicity via activating OrfXs/P47.
Article in Nature structural & molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- A belt-buckle checkpoint regulates the onset of botulinum neurotoxin intoxication.Nature communications · 2026Article
- Enteric botulinum neurotoxins facilitate infection byScience advances · 2026Article
- From Gut to Systemic Circulation: Molecular Strategies of Botulinum Neurotoxin Complexes.Toxins · 2026Review
- Advances in Clostridial Neurotoxins: Passage of the Intestinal Barrier and Targeting of Specific Neuronal Cells.Toxins · 2026Review
- Gut mucin fucosylation dictates the entry of botulinum toxin complexes.Nature communications · 2025Article
- Identification and characterization of botulinum neurotoxin-like two-component toxins inScience advances · 2025Article
- Article
- Gut mucin fucosylation dictates the entry of botulinum toxin complexes.bioRxiv : the preprint server for biology · 2025Article
- Structure of the complete 14-subunit botulinum neurotoxin B complex reveals a unique anchoring through the narrow central pore of HA70.Science advances · 2025Article
- A nut-and-bolt assembly of the bimodular large progenitor botulinum neurotoxin complex.Science advances · 2025Article
- Botulinum Neurotoxins: History, Mechanism, and Applications. A Narrative Review.Journal of neurochemistry · 2025Review
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Authors and funding
16 authors.
Funding
Abstract
Botulinum neurotoxins (BoNTs) rank among the most potent toxins and many of them are produced by bacteria carrying the orfX gene cluster that also encodes four nontoxic proteins (OrfX1, OrfX2, OrfX3 and P47). The orfX gene cluster is also found in the genomes of many non-BoNT-producing bacteria, often alongside genes encoding oral insecticidal toxins. However, the functions of these OrfXs and P47 remain elusive. Here, we demonstrate that the combined action of all four components (OrfXs and P47) drastically boosts the oral toxicity of BoNT in mice, following proteolytic activation by digestive proteases that oral toxins regularly confront. In particular, OrfX2 adopts a self-inhibiting state, engaging with BoNT through another clostridial protein, nontoxic non-hemagglutinin (NTNH), only after proteolytic activation. Cryo-electron microscopy studies unveil that two molecules of protease-activated OrfX2 simultaneously associate with NTNH, a binding mode crucial for boosting BoNT oral toxicity. Collectively, these studies offer novel insights into the physiological functions and regulatory mechanisms of OrfXs and P47 of BoNTs, shedding light on the pathogenesis of other bacterial toxins associated with homologous OrfXs and P47.
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