Channels formed by subnanomolar concentrations of the toxin aerolysin trigger apoptosis of T lymphomas.
Aerolysin is a channel-forming toxin that binds to glycosylphosphatidylinositol (GPI)-anchored proteins, such as Thy-1, on target cells. Here, we show that subnanomolar concentrations of aerolysin trigger apoptosis of T lymphomas. Using inactive aerolysin variants, we determined that apoptosis was not directly triggered by binding to GPI-anchored receptors, nor was it caused by receptor clustering induced by toxin oligomerization. Apoptosis was caused by the production of a small number of channels in the cell membrane. Channel formation resulted in a rapid increase in intracellular calcium, which may have been the signal for apoptosis. Overexpression of the antiapoptotic protein bcl-2 blocked aerolysin-induced apoptosis, although this effect was overcome at higher toxin concentrations.
Nelson
K L
KL
Department of Biochemistry and Microbiology, University of Victoria, BC, Canada.
Brodsky
R A
RA
Buckley
J T
JT
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006460:Hemolysin Proteins / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism*; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins; C032676:aerolysin; D002118:Calcium