The proapoptotic Bax protein induces cell death by acting on mitochondria. Bax binds to the permeability transition pore complex (PTPC), a composite proteaceous channel that is involved in the regulation of mitochondrial membrane permeability. Immunodepletion of Bax from PTPC or purification of PTPC from Bax-deficient mice yielded a PTPC that could not permeabilize membranes in response to atractyloside, a proapoptotic ligand of the adenine nucleotide translocator (ANT). Bax and ANT coimmunoprecipitated and interacted in the yeast two-hybrid system. Ectopic expression of Bax induced cell death in wild-type but not in ANT-deficient yeast. Recombinant Bax and purified ANT, but neither of them alone, efficiently formed atractyloside-responsive channels in artificial membranes. Hence, the proapoptotic molecule Bax and the constitutive mitochondrial protein ANT cooperate within the PTPC to increase mitochondrial membrane permeability and to trigger cell death.

The Gram-negative bacterial pathogen Shigella flexneri causes dysentery by invading the human colonic mucosa. Bacteria are phagocytosed by enterocytes, escape from the phagosome into the cytoplasm and spread to adjacent cells. After crossing the epithelium, Shigella reaches the lamina propria of intestinal villi, the first line of defence. This tissue is densely populated with phagocytes that are killed in great numbers, resulting in abscesses. The genes required for cell invasion and macrophage killing are located on a 220-kilobase plasmid. We report here on the mechanism of cytotoxicity used by S. flexneri to kill macrophages. Each of four different strains was tested for its capacity to induce cell death. An invasive strain induced programmed cell death (apoptosis), whereas its non-invasive, plasmidcured isogenic strain was not toxic; neither was a mutant in ipa B (ref. 10) (invasion protein antigen), a gene necessary for entry. A non-invasive strain expressing the haemolysin operon of Escherichia coli induced accidental cell death (necrosis), demonstrating that other bacterial cytotoxic mechanisms do not lead to apoptosis. This is the first evidence that an invasive bacterial pathogen can induce suicide in its host cells.

Summary The budding yeast, Saccharomyces cerevisiae, has emerged as an archetype of eukaryotic cell biology. Here we show that S. cerevisiae is also a model for the evolution of cooperative behavior by revisiting flocculation, a self-adherence phenotype lacking in most laboratory strains. Expression of the gene FLO1 in the laboratory strain S288C restores flocculation, an altered physiological state, reminiscent of bacterial biofilms. Flocculation protects the FLO1-expressing cells from multiple stresses, including antimicrobials and ethanol. Furthermore, FLO1+ cells avoid exploitation by non-expressing flo1 cells by self/non-self recognition: FLO1+ cells preferentially stick to one another, regardless of genetic relatedness across the rest of the genome. Flocculation, therefore, is driven by one of a few known “green beard genes”, which direct cooperation towards other carriers of the same gene. Moreover, FLO1 is highly variable among strains both in expression and in sequence, suggesting that flocculation in S. cerevisiae is a dynamic, rapidly-evolving social trait.