title: The multiple mechanisms of Ca2+ signalling by listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes.
abstract: Cholesterol-dependent cytolysins (CDCs) represent a large family of conserved pore-forming toxins produced by several Gram-positive bacteria such as Listeria monocytogenes, Streptococcus pyrogenes and Bacillus anthracis. These toxins trigger a broad range of cellular responses that greatly influence pathogenesis. Using mast cells, we demonstrate that listeriolysin O (LLO), a prototype of CDCs produced by L. monocytogenes, triggers cellular responses such as degranulation and cytokine synthesis in a Ca(2+)-dependent manner. Ca(2+) signalling by LLO is due to Ca(2+) influx from extracellular milieu and release of from intracellular stores. We show that LLO-induced release of Ca(2+) from intracellular stores occurs via at least two mechanisms: (i) activation of intracellular Ca(2+) channels and (ii) a Ca(2+) channels independent mechanism. The former involves PLC-IP(3)R operated Ca(2+) channels activated via G-proteins and protein tyrosine kinases. For the latter, we propose a novel mechanism of intracellular Ca(2+) release involving injury of intracellular Ca(2+) stores such as the endoplasmic reticulum. In addition to Ca(2+) signalling, the discovery that LLO causes damage to an intracellular organelle provides a new perspective in our understanding of how CDCs affect target cells during infection by the respective bacterial pathogens.
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. nelson.gekara@helmholtz-hzi.de
authors.forename: Nelson O
authors.initials: NO
authors.lastname: Gekara
authors.forename: Kathrin
authors.initials: K
authors.lastname: Westphal
authors.forename: Bin
authors.initials: B
authors.lastname: Ma
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: Lothar
authors.initials: L
authors.lastname: Groebe
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D002784:Cholesterol / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000494:pharmacology / Q000502:physiology*; D006460:Hemolysin Proteins / Q000494:pharmacology / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D008089:Listeria monocytogenes / Q000502:physiology*; D008407:Mast Cells / Q000378:metabolism / Q000382:microbiology / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D015220:Calcium Channels; D016207:Cytokines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002784:Cholesterol; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; C038705:hlyA protein, Listeria monocytogenes; D002118:Calcium