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. 2007 Jul;9(7):1753-65.
doi: 10.1111/j.1462-5822.2007.00911.x. Epub 2007 Mar 8.

Bacteriophage-encoded Toxins: The Lambda-Holin Protein Causes Caspase-Independent Non-Apoptotic Cell Death of Eukaryotic Cells

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Bacteriophage-encoded Toxins: The Lambda-Holin Protein Causes Caspase-Independent Non-Apoptotic Cell Death of Eukaryotic Cells

Chukwuma A Agu et al. Cell Microbiol. .

Abstract

The bacteriophage-encoded holin proteins are known to promote bacterial cell lysis by forming lesions within the cytoplasmic membrane. Recently, we have shown that the bacteriophage lambda-holin protein exerts cytotoxic activity also in eukaryotic cells accounting for a reduced tumour growth in vivo. In order to elucidate the mechanisms of lambda-holin-induced mammalian cell death, detailed biochemical and morphological analyses were performed. Colocalization analyses by subcellular fractionation and organelle-specific fluorescence immunocytochemistry indicated the presence of the lambda-holin protein in the endoplasmic reticulum and in mitochondria. Functional studies using the mitochondria-specific fluorochrome JC-1 demonstrated a loss of mitochondrial transmembrane potential in response to lambda-holin expression. Morphologically, these cells exhibited unfragmented nuclei but severe cytoplasmic vacuolization representing signs of oncosis/necrosis rather than apoptosis. Consistently, Western blot analyses indicated neither an activation of effector caspases 3 and 7 nor cleavage of the respective substrate poly(ADP-ribose) polymerase (PARP) in an apoptosis-specific manner. These findings suggest that the lambda-holin protein mediates a caspase-independent non-apoptotic mode of cell death.

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