<i>Legionella pneumophila</i>
            inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family

Banga, Simran; Gao, Ping; Shen, Xihui; Fiscus, Valena; Zong, Wei Xing; Chen, Lingling; Luo, Zhao‐Qing

doi:10.1073/pnas.0611030104

Cited by 203 publications

(197 citation statements)

References 32 publications

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“…SidF has been shown to play a role in conferring cell death resistance in infected macrophages by interacting through its Cterminal portion with BNIP3 and Bcl-rambo, two prodeath members of the Bcl2 protein family (24). Here, we further show that the N-terminal part of SidF is a specific PI-3-phosphatase.…”

Section: Discussionmentioning

confidence: 62%

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Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase

Hsu

Zhu

Brennan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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104

113

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Legionella pneumophila is an opportunistic intracellular pathogen that causes sporadic and epidemic cases of Legionnaires' disease. Emerging data suggest that Legionella infection involves the subversion of host phosphoinositide (PI) metabolism. However, how this bacterium actively manipulates PI lipids to benefit its infection is still an enigma. Here, we report that the L. pneumophila virulence factor SidF is a phosphatidylinositol polyphosphate 3-phosphatase that specifically hydrolyzes the D3 phosphate of PI(3,4)P 2 and PI(3,4,5)P 3 . This activity is necessary for anchoring of PI(4)Pbinding effectors to bacterial phagosomes. Crystal structures of SidF and its complex with its substrate PI(3,4)P 2 reveal striking conformational rearrangement of residues at the catalytic site to form a cationic pocket that specifically accommodates the D4 phosphate group of the substrate. Thus, our findings unveil a unique Legionella PI phosphatase essential for the establishment of lipid identity of bacterial phagosomes.phosphoinositide signaling | phagocytosis | membrane trafficking | type IV secretion system | virulence factor

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Section: Discussionmentioning

confidence: 62%

“…Some of these proteins were then expressed, purified, and examined for in vitro PI phosphatase activities by a malachite green-based assay (23). SidF, a Dot/Icm substrate shown to be involved in modulating host cell death (24), was found to possess PI phosphatase activity (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase

Hsu

Zhu

Brennan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

113

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“…Apparently, SidF would abolish the activities of two proapoptotic proteins members of the Bcl-2 family: BNIP3 and Bcl-rambo. 42 Similarly, recent studies show that Cb inhibits apoptosis induction in host cells and this effect is mediated by the bacterial protein synthesis. 34,35 Cumulative evidence indicates that apoptosis and autophagy are interconnected pathways, implying that a common stimulus triggers the response of both pathways or that the activation of one of them excludes the other.…”

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection

Vázquez

Colombo

2009

Cell Death Differ

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Coxiella burnetii is the etiological agent of the human disease, Q fever, and is an obligate intracellular bacterium that invades and multiplies in a vacuole with lysosomal characteristics. We have previously shown that Coxiella interacts with the autophagic pathway as a strategy for its survival and replication. In addition, recent studies have shown that Coxiella exerts anti-apoptotic activity to maintain the host cell viability, thus generating a persistent infection. In the present report, we have explored the role of Beclin 1 and Bcl-2 in C. burnetii infection to elucidate how this bacterium modulates autophagy and apoptosis to its own benefit. Beclin 1, a Bcl-2 interacting protein, is required for autophagy. In this study, we show that Beclin 1 is recruited to the Coxiella-membrane vacuole, favoring its development and bacterial replication. In contrast, the anti-apoptotic protein Bcl-2 alters the normal development of the Coxiella-replicative compartment, in spite of also being recruited to the vacuole membrane. Furthermore, both vacuole development and the anti-apoptotic effect of C. burnetii are affected by Beclin 1 depletion and by the expression of a Beclin 1 mutant defective in Bcl-2 binding. Overall, these findings indicate that C. burnetii infection modulates autophagy and apoptotic pathways through Beclin 1/Bcl-2 interplay to establish a successful infection in the host cell.

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“…Various strategies have led to the identification of more than 150 protein substrates for the L. pneumophila T4SS (5-7). These proteins are predicted to modulate various host processes, including apoptosis, ubiquitination (8)(9)(10), lipid metabolism, and membrane trafficking (6,(11)(12)(13). By combining bioinformatics tools with the use of Legionella as a surrogate host to measure protein translocation, 11 Coxiella proteins containing the ankyrin repeat motif have been identified as substrates of its Dot/ Icm transporter (11,14).…”

mentioning

confidence: 99%

Large-scale identification and translocation of type IV secretion substrates by Coxiella burnetii

Chen

Banga²,

Mertens³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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178

259

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Coxiella burnetii is an obligate intracellular bacterial pathogen responsible for acute and chronic Q fever. This bacterium harbors a type IV secretion system (T4SS) highly similar to the Dot/Icm of Legionella pneumophila that is believed to be essential for its infectivity. Protein substrates of the Coxiella T4SS are predicted to facilitate the biogenesis of a phagosome permissive for its intracellular growth. However, due to the lack of genetic systems, protein transfer by the C. burnetii Dot/Icm has not been demonstrated. In this study, we report the identification of 32 substrates of the C. burnetii Dot/Icm system using a fluorescence-based β-lactamase (TEM1) translocation assay as well as the calmodulin-dependent adenylate cyclase (CyaA) assay in the surrogate host L. pneumophila. Notably, 26 identified T4SS substrates are hypothetical proteins without predicted function. Candidate secretion substrates were obtained by using (i) a genetic screen to identify C. burnetii proteins interacting with DotF, a component of the T4SS, and (ii) bioinformatic approaches to retrieve candidate genes that harbor characteristics associated with previously reported substrates of the Dot/Icm system from both C. burnetii and L. pneumophila. Moreover, we have developed a shuttle plasmid that allows the expression of recombinant proteins in C. burnetii as TEM fusion products. Using this system, we demonstrated that a Dot/Icm substrate identified with L. pneumophila was also translocated by C. burnetii in a process that requires its C terminus, providing direct genetic evidence of a functional T4SS in C. burnetii.effectors | protein translocation | transporter

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Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family

Cited by 203 publications

References 32 publications

Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase

Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase

Coxiella burnetii modulates Beclin 1 and Bcl-2, preventing host cell apoptosis to generate a persistent bacterial infection

Large-scale identification and translocation of type IV secretion substrates by Coxiella burnetii

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