title: The lipopeptide toxins anabaenolysin A and B target biological membranes in a cholesterol-dependent manner.
abstract: The two novel cyanobacterial cyclic lipopeptides, anabaenolysin (Abl) A and B permeabilised mammalian cells, leading to necrotic death. Abl A was a more potent haemolysin than other known biodetergents, including digitonin, and induced discocyte-echinocyte transformation in erythrocytes. The mitochondria of the dead cells appeared intact with regard to both ultrastructure and membrane potential. Also isolated rat liver mitochondria were resistant to Abl, judged by their ultrastructure and lack of cytochrome c release. The sparing of the mitochondria could be related to the low cholesterol content of their outer membrane. In fact, a supplement of cholesterol in liposomes sensitised them to Abl. In contrast, the prokaryote-directed cyclic lipopeptide surfactin lysed preferentially non-cholesterol-containing membranes. In silico comparison of the positions of relevant functional chemical structures revealed that Abl A matched poorly with surfactin in spite of the common cyclic lipopeptide structure. Abl A and the plant-derived glycolipid digitonin had, however, predicted overlaps of functional groups, particularly in the cholesterol-binding tail of digitonin. This may suggest independent evolution of Abl and digitonin to target eukaryotic cholesterol-containing membranes. Sub-lytic concentrations of Abl A or B allowed influx of propidium iodide into cells without interfering with their long-term cell viability. The transient permeability increase allowed the influx of enough of the cyanobacterial cyclic peptide toxin nodularin to induce apoptosis. The anabaenolysins might therefore not only act solely as lysins, but also as cofactors for the internalisation of other toxins. They represent a potent alternative to digitonin to selectively disrupt cholesterol-containing biological membranes.
authors: Department of Biomedicine, University of Bergen, Norway.
authors: Linn
authors: L
authors: Oftedal
authors: Lene
authors: L
authors: Myhren
authors: Jouni
authors: J
authors: Jokela
authors: Gro
authors: G
authors: Gausdal
authors: Kaarina
authors: K
authors: Sivonen
authors: Stein Ove
authors: SO
authors: Døskeland
authors: Lars
authors: L
authors: Herfindal
mesh_terms: D017033:Anabaena; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002784:Cholesterol / Q000378:metabolism*; D045304:Cytochromes c; D004072:Digitonin / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006460:Hemolysin Proteins / Q000737:chemistry / Q000378:metabolism*; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008930:Mitochondria, Liver / Q000378:metabolism; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011419:Propidium; D051381:Rats
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D055666:Lipopeptides; D008081:Liposomes; D010456:Peptides, Cyclic; C063998:nodularin; C009365:surfactin peptide; D011419:Propidium; D045304:Cytochromes c; D002784:Cholesterol; D004072:Digitonin