ArticlePLoS pathogens2016
Clostridium difficile Toxin A Undergoes Clathrin-Independent, PACSIN2-Dependent Endocytosis.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 43 citations in OpenAlex.
- From colonization to infection: Genomic evolution of Clostridioides difficile pathogenesis.Cell reports · 2026Review
- Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin.Archives of toxicology · 2026Review
- The antimicrobial peptide Angie 5 inhibits TcdA and TcdB from Clostridioides difficile.Cellular and molecular life sciences : CMLS · 2025Article
- Article
- Mechanisms ofFrontiers in cellular and infection microbiology · 2025Review
- Positive Intervention of Distinct Peptides in Clostridioides difficile Infection in a Mouse Model.Communications biology · 2024Article
- Exploring the Toxin-Mediated Mechanisms inMicroorganisms · 2024Review
- Article
- Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells.Journal of cell science · 2023Article
- Review
- Redistribution of the Novel Clostridioides difficile Spore Adherence Receptor E-Cadherin by TcdA and TcdB Increases Spore Binding to Adherens Junctions.Infection and immunity · 2023Article
- Capturing the environment of the Clostridioides difficile infection cycle.Nature reviews. Gastroenterology & hepatology · 2022Review
- Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics.Nature reviews. Microbiology · 2022Review
- PACSIN proteins in vivo: Roles in development and physiology.Acta physiologica (Oxford, England) · 2022Review
- Syndapin-2 mediated transcytosis of amyloid-β across the blood-brain barrier.Brain communications · 2022Article
- Large Clostridial Toxins: Mechanisms and Roles in Disease.Microbiology and molecular biology reviews : MMBR · 2021Review
- Review
- Binding and neutralization of C. difficile toxins A and B by purified clinoptilolite-tuff.PloS one · 2021Article
- Review
- PACSIN2 Interacts with Nonstructural Protein 5A and Regulates Hepatitis C Virus Assembly.Journal of virology · 2020Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Clostridium difficile infection affects a significant number of hospitalized patients in the United States. Two homologous exotoxins, TcdA and TcdB, are the major virulence factors in C. difficile pathogenesis. The toxins are glucosyltransferases that inactivate Rho family-GTPases to disrupt host cellular function and cause fluid secretion, inflammation, and cell death. Toxicity depends on receptor binding and subsequent endocytosis. TcdB has been shown to enter cells by clathrin-dependent endocytosis, but the mechanism of TcdA uptake is still unclear. Here, we utilize a combination of RNAi-based knockdown, pharmacological inhibition, and cell imaging approaches to investigate the endocytic mechanism(s) that contribute to TcdA uptake and subsequent cytopathic and cytotoxic effects. We show that TcdA uptake and cellular intoxication is dynamin-dependent but does not involve clathrin- or caveolae-mediated endocytosis. Confocal microscopy using fluorescently labeled TcdA shows significant colocalization of the toxin with PACSIN2-positive structures in cells during entry. Disruption of PACSIN2 function by RNAi-based knockdown approaches inhibits TcdA uptake and toxin-induced downstream effects in cells indicating that TcdA entry is PACSIN2-dependent. We conclude that TcdA and TcdB utilize distinct endocytic mechanisms to intoxicate host cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.