
Induction of caspase 3 activation by multiple L egionella pneumophila Dot / Icm substrates
Author(s) -
Zhu Wenhan,
Hammad Loubna A.,
Hsu FoSheng,
Mao Yuxin,
Luo ZhaoQing
Publication year - 2013
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12157
Subject(s) - biology , microbiology and biotechnology , nlrp1 , legionella pneumophila , caspase 10 , caspase , cytochrome c , apoptosis , programmed cell death , intracellular , caspase 3 , mitochondrion , caspase 2 , effector , biochemistry , bacteria , genetics
Summary The intracellular pathogen L egionella 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 A 2, 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.