Heterodimeric integrin complexes containing beta1-integrin promote internalization and lethality of anthrax toxin
Mikhail Martchenko1, Sun-Young Jeong, Stanley N Cohen
1Departments of Genetics and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Summary
Integrin beta1 acts as a crucial co-receptor for Bacillus anthracis toxin entry into cells, enhancing its lethal effects. This finding reveals a new mechanism for anthrax toxin
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Bacillus anthracis toxin uses protective antigen (PA) to bind cell receptors like CMG2 for entry.
- CMG2 and TEM8 receptors, containing von Willebrand A domains, are key for PA binding and toxin endocytosis.
- Macrophages are primary targets for anthrax toxin, leading to cell death.
Purpose of the Study:
- To investigate the role of integrin beta1 in Bacillus anthracis toxin endocytosis and lethality.
- To identify novel cellular factors involved in anthrax toxin entry and sensitivity.
- To understand the synergistic effects of CMG2 and integrin pathways in toxin-mediated cell death.
Main Methods:
- Microarray analysis to correlate gene expression with toxin sensitivity.
- Co-immunoprecipitation and in vitro binding assays to study PA-integrin interactions.
- Monoclonal antibody inhibition and small molecule interference to assess functional roles.
- Cell viability assays to determine toxin-induced lethality in wild-type and deficient cells.
Main Results:
- Integrin beta1, along with osteopontin and CD44, was identified as a mediator of anthrax toxin endocytosis.
- PA binds to alpha4beta1 and alpha5beta1 integrin complexes, facilitating their co-endocytosis.
- Inhibition of beta1-integrin or its partners reduced toxin entry and lethality.
- Integrin function was essential for late-stage killing of macrophages, particularly in CMG2-deficient cells or at low toxin doses.
Conclusions:
- Beta1-integrin acts as a low-affinity PA receptor and potentiates CMG2-mediated anthrax toxin endocytosis.
- Integrin-mediated pathways contribute significantly to anthrax toxin lethality, especially under specific conditions.
- Targeting integrin function offers a potential strategy to combat anthrax toxin effects.
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