title: Induction of caspase 3 activation by multiple Legionella pneumophila Dot/Icm substrates.
abstract: The intracellular pathogen Legionella pneumophila is able to strike a balance between the death and survival of the host cell during infection. Despite the presence of high level of active caspase 3, the executioner caspase of apoptotic cell death, infected permissive macrophages are markedly resistant to exogenous apoptotic stimuli. Several bacterial molecules capable of promoting the cell survival pathways have been identified, but proteins involved in the activation of caspase 3 remain unknown. To study the mechanism of L. pneumophila-mediated caspase 3 activation, we tested all known Dot/Icm substrates for their ability to activate caspase 3. Five effectors capable of causing caspase 3 activation upon transient expression were identified. Among these, by using its ability to activate caspase 3 by inducing the release of cytochrome c from the mitochondria, we demonstrated that VipD is a phospholipase A2, which hydrolyses phosphatidylethanolamine (PE) and phosphocholine (PC) on the mitochondrial membrane in a manner that appears to require host cofactor(s). The lipase activity leads to the production of free fatty acids and 2-lysophospholipids, which destabilize the mitochondrial membrane and may contribute to the release of cytochrome c and the subsequent caspase 3 activation. Furthermore, we found that whereas it is not detectably defectively in caspase 3 activation in permissive cells, amutant lacking all of these five genes is less potent in inducing apoptosis in dendritic cells. Our results reveal that activation of host cell death pathways by L. pneumophila is a result of the effects of multiple bacterial proteins with diverse biochemical functions.
authors.affiliation: Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN, 47907, USA.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Zhu
authors.forename: Loubna A
authors.initials: LA
authors.lastname: Hammad
authors.forename: Fosheng
authors.initials: F
authors.lastname: Hsu
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
authors.forename: Zhao-Qing
authors.initials: ZQ
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000096:biosynthesis*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D016952:Legionella pneumophila / Q000378:metabolism*; D051379:Mice; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors; D053148:Caspase 3