ArticleThe Journal of biological chemistry2012
Leukotoxin (Leukothera®) targets active leukocyte function antigen-1 (LFA-1) protein and triggers a lysosomal mediated cell death pathway.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 55 citations in OpenAlex.
- Review
- Leveraging the active conformation of LFA-1 as a potential target for hematological malignancies.Molecular therapy. Methods & clinical development · 2025Article
- Phosphorylation of the βScientific reports · 2025Article
- The Role of Reactive Oxygen Species (ROS) in Periodontitis: A Potential Therapeutic Target.Immunity, inflammation and disease · 2025Review
- Periodontal pathogens and cancer development.Periodontology 2000 · 2024Review
- Caspase-11 mediated inflammasome activation in macrophages by systemic infection of A. actinomycetemcomitans exacerbates arthritis.International journal of oral science · 2024Article
- Therapeutic Applications ofPathogens (Basel, Switzerland) · 2024Review
- Heterogeneity of Size and Toxin Distribution inToxins · 2024Article
- Article
- Leukotoxin (LtxA/Leukothera) induces ATP expulsion via pannexin-1 channels and subsequent cell death in malignant lymphocytes.Scientific reports · 2021Article
- Periodontitis Exacerbates and Promotes the Progression of Chronic Kidney Disease Through Oral Flora, Cytokines, and Oxidative Stress.Frontiers in microbiology · 2021Review
- Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti-toxin therapeutics.Molecular oral microbiology · 2020Review
- Article
- Article
- Review
- Virulence and Pathogenicity Properties ofPathogens (Basel, Switzerland) · 2019Review
- Article
- Review
- Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA) Requires Death Receptor Fas, in Addition to LFA-1, To Trigger Cell Death in T Lymphocytes.Infection and immunity · 2019Article
- Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote.Nature communications · 2019Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leukotoxin (LtxA) is a protein toxin that is secreted from the oral bacterium, Aggregatibacter actinomycetemcomitans. LtxA targets specifically the β(2) integrin, leukocyte function antigen-1 (LFA-1) on white blood cells (WBCs) and causes cell death. LtxA preferentially targets activated WBCs and is being developed as a therapeutic agent for the treatment of WBC diseases such as hematologic malignancies and autoimmune/inflammatory diseases. However, the mechanism by which interaction between LtxA and LFA-1 results in cell death is not well understood. Furthermore, how LtxA preferentially recognizes activated WBCs is not known. We show here that LtxA interacts specifically with LFA-1 in the active (exposed) conformation. In THP-1 monocytes, LtxA caused rapid activation of caspases, but LtxA could overcome the inhibition of caspases and still intoxicate. In contrast, inhibiting the vesicular trafficking pathway or cathepsin D release from the lysosome resulted in significant inhibition of LtxA-mediated cytotoxicity, indicating a more potent, lysosomal mediated cell death pathway. LtxA caused rapid disruption of the lysosomal membrane and release of lysosomal contents into the cytosol. Binding of LtxA to LFA-1 resulted in the internalization of both LtxA and LFA-1, with LtxA localizing specifically to the lysosomal compartment. To our knowledge, LtxA represents the first bacterial toxin shown to localize to the lysosome where it induces rapid cell death.
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