ArticleInfection and immunity2015
A Heterologous Reporter Defines the Role of the Tetanus Toxin Interchain Disulfide in Light-Chain Translocation.
Article in Infection and immunity, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Structure and functional divergence of the non-canonical BoNT-like toxin PG1 and PG2.Nature communications · 2026Article
- Sphingolipid metabolic enzyme GLA expression in gliomas: prognostic implications and therapeutic potential.Frontiers in oncology · 2026Article
- Disulphide bond-forming enzymes in clostridial species.Microbiology (Reading, England) · 2025Article
- How Botulinum Neurotoxin Light Chain A1 Maintains Stable Association with the Intracellular Neuronal Plasma Membrane.Toxins · 2022Article
- Article
- The Cytotoxic Necrotizing Factors (CNFs)-A Family of Rho GTPase-Activating Bacterial Exotoxins.Toxins · 2021Review
- Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane.International journal of molecular sciences · 2021Article
- Structural flexibility of the tetanus neurotoxin revealed by crystallographic and solution scattering analyses.Journal of structural biology: X · 2021Article
- Tetanus ToxinmSphere · 2020Article
- Resolving the Molecular Steps in Clostridial Neurotoxin Light Chain Translocation.Journal of experimental neurology · 2020Article
- The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs.Cellular microbiology · 2019Review
- Involvement of Hsp90 and cyclophilins in intoxication by AIP56, a metalloprotease toxin from Photobacterium damselae subsp. piscicida.Scientific reports · 2019Article
- Protein Toxins That Utilize Gangliosides as Host Receptors.Progress in molecular biology and translational science · 2018Review
- Protein Structure Facilitates High-Resolution Immunological Mapping.Clinical and vaccine immunology : CVI · 2017Review
- The structure of the tetanus toxin reveals pH-mediated domain dynamics.EMBO reports · 2017Article
- Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.Pharmacological reviews · 2017Review
- From GFP to β-lactamase: advancing intact cell imaging for toxins and effectors.Pathogens and disease · 2015Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Botulinum neurotoxins (BoNTs) and tetanus toxin (TeNT) are the most potent toxins for humans and elicit unique pathologies due to their ability to traffic within motor neurons. BoNTs act locally within motor neurons to elicit flaccid paralysis, while retrograde TeNT traffics to inhibitory neurons within the central nervous system (CNS) to elicit spastic paralysis. BoNT and TeNT are dichain proteins linked by an interchain disulfide bond comprised of an N-terminal catalytic light chain (LC) and a C-terminal heavy chain (HC) that encodes an LC translocation domain (HCT) and a receptor-binding domain (HCR). LC translocation is the least understood property of toxin action, but it involves low pH, proteolysis, and an intact interchain disulfide bridge. Recently, Pirazzini et al. (FEBS Lett 587:150-155, 2013, http://dx.doi.org/10.1016/j.febslet.2012.11.007) observed that inhibitors of thioredoxin reductase (TrxR) blocked TeNT and BoNT action in cerebellar granular neurons. In the current study, an atoxic TeNT LC translocation reporter was engineered by fusing β-lactamase to the N terminus of TeNT [βlac-TeNT(RY)] to investigate LC translocation in primary cortical neurons and Neuro-2a cells. βlac-TeNT(RY) retained the interchain disulfide bond, showed ganglioside-dependent binding to neurons, required acidification to promote βlac translocation, and was sensitive to auranofin, an inhibitor of thioredoxin reductase. Mutation of βlac-TeNT(RY) at C439S and C467S eliminated the interchain disulfide bond and inhibited βlac translocation. These data support the requirement of an intact interchain disulfide for LC translocation and imply that disulfide reduction is a prerequisite for LC delivery into the host cytosol. The data also support a model that LC translocation proceeds from the C to the N terminus. βlac-TeNT(RY) is the first reporter system to measure translocation by an AB single-chain toxin in intact cells.
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